RARE DISEASE
Adult T-cell leukemia/lymphoma
Adult T-cell leukemia/lymphoma
Adult T-cell leukemia/lymphoma
Synonyms: ATLL
Synonyms: ATLL
Synonyms: ATLL
Drug discovery
6
drugs
With orphan designations
Overview
Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive HTLV-1-associated T-cell malignancy with four clinical subtypes (acute, lymphoma, chronic, smoldering). It arises from clonal expansion of HTLV-1-infected CD4+ T-cells after decades of viral latency, typically presenting with leukemic cells, lymphadenopathy, hypercalcemia, and opportunistic infections. Prognosis remains poor (median survival: <1 year for aggressive subtypes), though novel therapies and allo-HSCT may improve outcomes [1][3][6][12].
Population
Predominantly affects HTLV-1-endemic regions: Japan, Caribbean, Central/South America, and parts of Africa [1][7][12]
Higher incidence in males (1.4:1 ratio) and non-Hispanic Black populations; median age at diagnosis varies geographically (40–70 years) [2][7][17]
Lifetime risk: 2–5% of HTLV-1 carriers, increasing to >20% in high–proviral load carriers [1][7][12]
Burden
Mortality: 5-year survival <20% for acute/lymphoma subtypes despite treatment [1][7][12]
Geographic disparity: Rising incidence in high-risk US populations (e.g., Caribbean immigrants in NYC) [7][12]
High relapse rates and treatment costs due to chemotherapy resistance and frequent infections [1][6][17]
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,581 drug discovery papers about Adult T-cell leukemia/lymphoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,581 drug discovery papers about Adult T-cell leukemia/lymphoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Replication Stress Tolerance in Adult T-Cell Leukemia.
Replication stress (RS) represents a major vulnerability of cancer cells treated with nucleoside analogs and related antimetabolites; however, tumors frequently acquire tolerance mechanisms that permit survival despite persistent DNA lesions. This review examines molecular determinants of RS tolerance, focusing on human T-cell leukemia virus type 1 (HTLV-1)-mediated adult T-cell leukemia/lymphoma (ATL) as a model of virus-mediated rewiring of DNA damage responses. Chain-terminating nucleoside analogs generate aberrant replication intermediates, including blocked 3' DNA termini, mis-incorporated bases, and stalled replication forks. In ATL, viral oncoproteins suppress key components of replication stress response pathways, notably tyrosyl-DNA phosphodiesterase 1 (TDP1) and mismatch repair (MMR), thereby creating exploitable repair deficiencies. Consistent with this vulnerability, ATL cells exhibit marked sensitivity to replication stress-inducing agents such as irinotecan (CPT-11) and the chain-terminating nucleoside analog abacavir. Recent CRISPR-based functional genomics studies further identify Schlafen 11 (SLFN11) as an independent and dominant regulator of RS sensitivity. SLFN11 determines the fate of stressed replication forks independently of lesion processing, acting as an execution factor that converts otherwise tolerable RS into irreversible replication arrest. We conclude by discussing therapeutic strategies that exploit RS tolerance defects in ATL, including biomarker-guided nucleoside analog therapy, and rational combination approaches targeting compensatory RS pathways.
2026-09-23 | Durable immunovirological control after sequential mogamulizumab and tucidinostat in relapsed or refractory adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive HTLV-1-associated T-cell neoplasm, and durable control of relapsed/refractory disease remains difficult without allogeneic hematopoietic stem cell transplantation. Mogamulizumab, an afucosylated anti-C-C chemokine receptor type 4 (CCR4) monoclonal antibody, and tucidinostat, an oral histone deacetylase inhibitor, have activity in this setting, but the immunovirological consequences of sequential CCR4-directed therapy and epigenetic modulation are unclear. We describe two patients with relapsed or refractory ATLL who achieved prolonged disease control after mogamulizumab/tucidinostat-based sequential therapy and underwent longitudinal monitoring of Tax301-309-specific CD8+ T cells, CD4/CD8 dynamics, HTLV-1 proviral DNA, and T-cell receptor (TCR) Vβ repertoire. Patient 1 had lymphoma-type ATLL with metabolic partial response after mogamulizumab plus EPOCH; tucidinostat was initiated 63 days after the final mogamulizumab dose. Tax301-309-specific CD8+ T cells increased from 0.03% at tucidinostat initiation to >0.8% during long-term follow-up, and disease control persisted for 32 months after tucidinostat initiation. Patient 2 had multiply relapsed ATLL and received four cycles of sequential mogamulizumab/tucidinostat, followed by rapid disappearance of circulating ATLL cells, normalization of soluble interleukin-2 receptor, and marked reduction of HTLV-1 proviral load from 565.7 copies/1,000 peripheral blood mononuclear cells to low levels. Disease control persisted for 17 months after treatment discontinuation. In both patients, TCR Vβ repertoire analysis showed memory CD8+ T-cell-predominant patterns, including expansion of a Vβ2 memory CD8+ T-cell population. These observations are hypothesis-generating and suggest that sequential tumor debulking, CCR4/Treg-axis modulation, and epigenetic treatment may create a context permissive for HTLV-1 antigen-specific cellular immune surveillance in selected patients with ATLL.
2026-09-10 | Outcomes of CHOP versus CHOEP/EPOCH in aggressive adult T-cell leukemia/lymphoma: an international cohort analysis.
Aggressive adult T-cell leukemia/lymphoma (ATL) subtypes (i.e., acute and lymphomatous) are rare diseases, and the conventional management with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has historically yielded poor outcomes. The benefit of etoposide-containing regimens (CHOEP/EPOCH) in the first-line setting is inconclusive. We compared the effectiveness of CHOEP/EPOCH versus CHOP in aggressive ATL. We conducted an international, multicenter retrospective cohort study among newly diagnosed patients with ATL during 2000-2023 across five Latin American countries and the United States. Study endpoints included overall response rate (ORR) and overall survival (OS). Propensity score weighting was used to balance the treatment groups, and findings are reported for each ATL subtype. Among 328 patients, 108 had acute ATL and 220 had lymphomatous ATL. In weighted analyses, CHOEP/EPOCH was not statistically associated with a higher ORR compared to CHOP in lymphomatous ATL (66% vs. 58%; Odds ratio [OR]=2.08, 95% confidence interval [CI]=0.76-5.75) or acute ATL (42% vs. 58%; OR=0.68, 95% CI=0.06-7.84). With a median follow-up of 34 months (interquartile range [IQR] 15-73) in lymphomatous ATL, CHOEP/EPOCH was associated with a higher 3-year OS (34% vs. 12%; HR=0.55, 95% CI=0.35-0.87). However, with a median follow-up of 63 months (IQR 16-110) in acute ATL, CHOEP/EPOCH was not associated with improved 3-year OS (8% vs. 11%; HR=0.95, 95% CI=0.51-1.77). In conclusion, CHOEP/EPOCH may be associated with improved survival in lymphomatous ATL, while results in acute ATL were inconclusive. These findings support the need for prospective interventional studies to validate the subtype-specific benefits.
2026-09-08 | HHV-6 Encephalitis Presenting With Severe SIADH and CO₂ Narcosis in Non-Transplant Smoldering Adult T-Cell Leukemia/Lymphoma
Objective:Rare coexistence of disease or pathology Background:Human herpesvirus 6 (HHV-6) encephalitis is best recognized after allogeneic hematopoietic stem cell transplantation but can also occur in non-transplant immunocompromised patients.Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) may precede or accompany HHV-6 encephalitis.Severe SIADH as an early dominant clue in non-transplant patients with smoldering adult T-cell leukemia/lymphoma (ATLL) is not fully described. Case Report:A 55-year-old woman with smoldering ATLL received systemic corticosteroid therapy for clinically diagnosed human T-cell leukemia virus type 1 (HTLV-1)-associated uveitis and was admitted for progressive pulmonary infection.Bronchoscopic specimens revealed polymicrobial infection, including Nocardia and Actinomyces; invasive pulmonary aspergillosis was also clinically suspected.Although pulmonary findings improved with antimicrobial and antifungal therapy, she developed nausea, acute impairment of consciousness, and severe SIADH-associated hyponatremia.Serum sodium decreased to 113 mmol/L, and consciousness did not adequately improve after sodium correction.Cerebrospinal fluid obtained by lumbar puncture on hospital day 13 showed HHV-6 DNA positivity (1.0 × 10 3 copies/mL).Brain magnetic resonance imaging demonstrated bilateral cortical and limbic abnormalities, supporting a clinical diagnosis of HHV-6 encephalitis.Ganciclovir was initiated on hospital day 15 along with sodium correction, tolvaptan, and supportive care.The patient subsequently developed hypercapnic respiratory failure and CO 2 narcosis requiring mechanical ventilation.Her neurologic and respiratory status gradually improved, and she was discharged on hospital day 53. Conclusions:In non-transplant patients with ATLL, corticosteroid exposure, and opportunistic infection, severe SIADH accompanied by new neurologic symptoms can be an early clue to HHV-6 encephalitis.Early recognition and prompt initiation of antiviral therapy may help to improve neurologic outcomes.
2026-08-13 | Rewiring of the Apoptotic Rheostat in HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of apoptotic pathways, which is a key determinant of long-term viral persistence and favors malignant transformation. This review describes the mechanisms through which HTLV-1 gene products, including Tax and HBZ, reprogram host-cell signaling controlling the "apoptotic rheostat", an integrated network connecting redox metabolism, and response to apoptotic cues and immune pressure. We also highlight emerging therapeutic strategies to restore sensitivity to apoptosis, including BH3-mimetic drugs and rational combination approaches. Deciphering how HTLV-1 reconfigures the apoptotic network provides a conceptual and therapeutic framework for targeting death pathway vulnerabilities in ATLL and potentially other hematological neoplasms.
antibodies
2026-05-01 | C51-15 Refractory, Pthrp-independent Hypercalcemic Crisis Unmasking Htlv-1-associated Adult T-cell Leukemia/lymphoma With Diffuse Osteolysis
Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL), driven by HTLV-1, frequently presents with hypercalcemia, often attributed to PTHrP; however, RANKL/cytokine-mediated osteoclast activation can cause PTHrP-independent hypercalcemia that is refractory to standard therapy. Case Presentation A 49-year-old woman (BMI 45.7; prior sleeve gastrectomy) presented with lethargy, weakness, dyspnea, and severe hypercalcemia (total Ca 19.7 mg/dL). The patient also had a similar admission in another hospital for hypercalcemia. Hypercalcemia recurred despite aggressive IV fluids, repeated calcitonin, and zoledronic acid. PTH and PTHrP were suppressed; vitamin D was low. Imaging showed bilateral axillary/pelvic/inguinal lymphadenopathy and diffuse osteolytic vertebral lesions. Peripheral blood flow cytometry revealed an aberrant CD4+/CD7−/CD5− T-cell population (19% of leukocytes) with HTLV-1 seropositivity, supporting ATLL. Bone marrow was markedly hypocellular; FISH for common myeloid/lymphoid neoplasia was negative. Hospitalization was notable for transient thrombocytopenia, morbilliform rash responsive to topical steroids/antihistamines, prerenal AKI resolving with fluids, and electrolyte losses (K/Mg/Phos) requiring repletion. She remained hemodynamically stable on room air with persistent sinus tachycardia. Given refractory hypercalcemia and new ATLL diagnosis, she was transferred to a tertiary center for chemotherapy ± stem-cell transplant. Discussion ATLL-associated hypercalcemia may occur despite suppressed PTHrP, via RANKL-dependent osteoclastogenesis driven by HTLV-1/Tax signaling; diffuse osteolysis can accompany this physiology. Recognition of PTH/PTHrP-independent hypercalcemia is crucial when standard therapy fails. In bisphosphonate-refractory cases, denosumab (RANKL blockade) is an evidence-supported next step but risks prolonged hypocalcemia, necessitating careful ICU/step-down monitoring and calcium/vitamin D repletion strategies. This case emphasizes a diagnostic/therapeutic framework for severe recurrent hypercalcemia with lymphadenopathy and bone lesions culminating in ATLL. Conclusion Refractory hypercalcemia with suppressed PTH/PTHrP should prompt evaluation for HTLV-1-related ATLL and RANKL-mediated osteolysis. Early multidisciplinary management and consideration of denosumab may be lifesaving. This abstract is funded by: None
2025-10-30 | Pathobiological link between CD30 and abnormal lymphocytes in adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is a T-cell malignancy with poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is characterized by the emergence of abnormal lymphocytes, represented by the so called "flower cell". However, the mechanisms by which these cells contribute to tumorigenic processes associated with HTLV-1 infection are not well understood. Recent reports have suggested that CD30, tumor necrosis factor receptor superfamily 8 plays a role in the generation of these abnormal lymphocytes, providing insight into the involvement of CD30 in the tumorigenic process of HTLV-1-infected cells. Since CD30 can be targeted with brentuximab vedotin (BV), an anti-CD30 antibody linked with monomethyl auristatin E, a tubulin toxin, it is essential to gain a deeper understanding of the functions of CD30 in HTLV-1-infected cells in order to develop effective strategies for treating and preventing ATLL. This review describes the current understanding of how CD30 impacts the development of ATLL in cells infected with HTLV-1, with a specific emphasis on the connection between CD30 and the generation of abnormal lymphocytes.
2025-10-21 | A Multicenter Real-World Retrospective Study for Brentuximab Vedotin, Cyclophosphamide, Doxorubicin, and Prednisolone for Previously Untreated Patients With CD30-Positive Adult T-Cell Leukemia-Lymphoma.
Adult T-cell leukemia-lymphoma (ATL) is a rare, aggressive malignancy prevalent in Japan, the Caribbean, and Central/South America. This multicenter retrospective study evaluated the effectiveness and safety of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisolone (BV-CHP) in patients aged ≥ 18 years with previously untreated CD30-positive ATL, verified through immunohistochemistry/flow cytometry, from six hospitals in Japan. Outcomes included overall response rate (ORR; primary outcome), overall survival (OS), progression-free survival (PFS), complete response rate (CRR), disease control rate (DCR), and safety. Subgroup analyses evaluated lesion site, ATL subtype, age, and CD30 expression. Of 46 screened patients, 36 (median age 71 years; 66.7% female) were analyzed and started BV-CHP between April 2020 and January 2024. CD30 positivity was confirmed in all patients. ORR was 86.1% (95% confidence interval [CI] 70.5-95.3), CRR 61.1% (95% CI 43.5-76.9), and DCR 91.7% (95% CI 77.5-98.3). ORR by lesion site (lymph nodes, peripheral blood, skin) was 93.8%, 90.9%, and 83.3%, respectively, by ATL subtype (acute, lymphoma) was 78.9% and 94.1%, respectively, and by age (≤ 70 years, > 70 years) was 84.6% and 87.0%, respectively. One patient with CD30 expression < 10% achieved a complete response; ORR was 73.7% in 19 patients with CD30 expression ≥ 10%. Median OS and PFS was 535 days (95% CI 343-not estimable) and 205 days (95% CI 166-279), respectively. Treatment-emergent adverse events of any grade and grade ≥ 3 both occurred in 88.9% of patients, with neutropenia, febrile neutropenia, and thrombocytopenia being most common. Among 11 patients who underwent allogeneic stem cell transplantation, two developed acute graft-versus-host disease; median PFS was 234 days (95% CI 168-343), compared with 180 days (95% CI 96-279) without transplantation. BV-CHP demonstrated high ORR and CRR across age groups and ATL subtypes with a manageable safety profile, supporting its potential use as a standard treatment option.
2025-09-17 | Extracellular CD30 Regulates Brentuximab Vedotin-Induced Cell Death in an Adult T-Cell Leukemia Cell Line.
Adult T-cell leukemia/lymphoma (ATL) is a malignant tumor of mature T lymphocytes induced by human T-cell leukemia virus 1, and it has a poor prognosis. Brentuximab vedotin (BV) is included in the treatment of CD30-positive ATL, but there are no predictive biomarkers for the treatment effects of BV. Serum soluble CD30 (sCD30) concentrations are increased in aggressive ATL at the time of diagnosis, but the effect of extracellular CD30 on BV-induced cell death in ATL is unknown. Similarly, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 possess CD30 sheddase activity in anaplastic large cell lymphoma, but this activity is unclear in ATL. In this study, we showed that sCD30 concentrations were associated with BV activity in ATL-associated cell lines. Extracellular vesicles, such as exosomes containing CD30, also inhibited BV activity. Furthermore, knockdown of ADAM10/17 significantly reduced sCD30 concentrations and increased BV-induced cell death. These results suggest that ADAM10 and ADAM17 are involved in sCD30 production in ATL. Furthermore, endogenous extracellular CD30, such as sCD30 and CD30-positive extracellular vesicles shed by ADAM10/17, may be involved in BV-induced cell death. Taken together, our findings suggest that extracellular CD30 concentrations, including CD30 on extracellular vesicles, are a useful biomarker for BV therapy in ATL.
2025-08-21 | Development of a silicon phthalocyanine analogue for near-infrared photoimmunotherapy and its application to HTLV-1-infected leukemic cells.
Near-infrared photoimmunotherapy (NIR-PIT) employing an antibody labeled with a silicon phthalocyanine dye, IR700, was approved as a minimally invasive treatment for unresectable recurrent head and neck cancer in Japan in 2020. However, further derivatization of IR700 is needed to increase the efficiency of cancer treatment. Here, we developed SiPc-1 as an IR700 analog, in which the linker was constructed using click chemistry to simplify the synthetic scheme and its position was switched from α to β on the benzene ring of phthalocyanine to eliminate intramolecular steric repulsion. We evaluated the cleavage rate of the water-soluble axial moieties of SiPc-1 upon photoirradiation, the cytotoxicity, and the morphological change (blebbing) of treated cells upon photoirradiation. We performed gene expression and protein expression analyses to find a target antigen selectively expressed on cells infected with human T-cell lymphotropic virus type 1 (HTLV-1), the causative virus of adult T-cell leukemia/lymphoma (ATL), and identified CD25 as a suitable target antigen. An anti-CD25 antibody, basiliximab, labeled with SiPc-1 (bas-SiPc-1) showed selective toxicity towards HTLV-1-infected cultured cells and ATL patients' peripheral blood mononuclear cells upon photoirradiation.
proteins
2026-06-12 | Kunxian Capsule Exerts Antitumor Effects by Activating the IL-17 Signaling Pathway to Inhibit the Proliferation, Apoptosis, Cell Cycle, and Induce Reactive Oxygen Species Production in C8166 Tumor Cells.
Kunxian capsule (KXJN), a patented traditional Chinese medicine used for autoimmune diseases, remains unexplored in oncology. This study investigated its potential antitumor effects against adult T-cell leukemia/lymphoma (A-ATL). Network pharmacology identified KXJN-related targets from TCMSP and UniProt, and A-ATLassociated DEGs from GEO. Candidate targets and pathways were analyzed via Microbiotics and String. In vitro validation used C8166 cells, assessing proliferation (MTT assay), apoptosis, cell cycle, ROS production (flow cytometry), and protein/mRNA expression (Western blot, RT-qPCR). A total of 106 potential targets of KXJN were identified against A-ATL, with core nodes (JUN, IL-6, TNF) linked to the IL-17 pathway and other pathways. KXJN dose- and time-dependently inhibited C8166 proliferation, promoted apoptosis, and increased ROS. It activated the IL-17 pathway, upregulating associated proteins (ACT1, IL-17RA, TRAF6), core targets (JUN, IL-6, TNF), and cytokines (CXCL1, CXCL2, CCL20). KXJN exerts antitumor effects on C8166 cells by suppressing proliferation, inducing apoptosis and ROS, activating IL-17 signaling, and modulating cell cycle progression. These findings highlight KXJN's potential in tumor therapy, though further in vitro and in vivo studies are required to elucidate its precise mechanisms.
2025-11-03 | Characterizing the biological function FOXO3 and its role as a predictive biomarker in HTLV-1 related adult T-cell leukemia-lymphoma
Abstract Adult T-cell leukemia-lymphoma (ATL) is a highly aggressive T cell malignancy with dismal prognosis caused by the human T-cell leukemia virus, type 1 (HTLV-1), which is prevalent in Japan, South America, and the Caribbean. Because of our geographic proximity to HTLV-1 endemic regions, ATL patients are commonly encountered in south Florida and northeast U.S.A. At least four clinical ATL subtypes have been recognized. The acute and lymphomatous lethal forms are by far the most common variants. The 4-year survival rates for lymphomatous and acute type ATL are less than 20%, with median survival less than 11 months. First-line treatment options include multi-agent cytotoxic chemotherapy and interferon-a (IFNa)-based therapy. We recently published a large genomic study of ATL found in the Western hemisphere (W-ATLL) and discovered mutational patterns that differed from Japanese patients [Myers and Choi group, Gru, and Ramos et al. Haematologica. 2024 Dec 1;109(12):4021-4039]. A notorious finding was the recurrence of novel FOXO3 mutations (R177W and D199N) mapping to the DNA binding domain in 10% of patients (17% of African-descent cases) with acute type ATL suggesting that the possible tumor suppressive function of FOXO3 in ATL requires DNA binding. In total, FOXO3 mutations or genomic deletions occurred at a frequency of ~20%. FOXO3 is a transcriptional activator, whose function is known to induce the expression of pro-apoptotic genes (i.e., BIM and FasL) and to promote drug-induced autophagy. FOXO3 protein has been demonstrated to be inactivated by phosphorylation via AKT and targeted by HTLV-1 bZip (HBZ) protein, which sequesters it in the nucleus while attenuating its pro-apoptotic function. W-ATL tumors analyzed from our cohort generally showed reduced FOXO3 protein expression, suggesting that dysregulated FOXO3 function could be an important oncogenic event in ATL development. Our preliminary in vitro studies using our patient derived ATL cell lines showed that overexpression of FOXO3 increased antineoplastic drug-induced apoptosis in ATL cells, while overexpression of R177W and D199N mutant forms and FOXO3 knock-out (KO) conferred resistance to anti-neoplastic drugs. More recently, our ATL cell lines were engineered to overexpress FOXO3 via more efficient transduction of tetracycline-inducible pRetroX vectors demonstrating FOXO3 slow the proliferation of ATL cells in vitro. We also correlated our published exome sequencing with patient outcomes (treatment response rates and survival) using our existing well-annotated database. Surprisingly, W-ATLL patients carrying mutated FOXO3 responded better to IFNa-based therapies after achieving a significantly higher complete response rate (37% vs. 16%) and longer progression-free survival (7 months vs. 0.9 months, p= 0.0172) (unpublished data). Thus, FOXO3 mutations may result in ATL forms that are perhaps more susceptible to immune-based therapies such as IFN which depend less on direct drug-induced apoptosis. Our current studies aim to confirm and define the functional role of FOXO3 in ATL and to evaluate the clinical implications of altered FOXO3 in this disease. Given our preliminary findings, we are investigating FOXO3 as a predictive biomarker in prospective ATL samples and characterizing its functional using our preclinical models.
2025-08-27 | MultiClass Machine Learning-based Identification of Anoikis-related Genes Across Three Adult T-cell Leukemia/Lymphoma Subtypes
Abstract Adult T-cell leukemia/lymphoma (ATLL) is a type of cancer that originates from T-cells infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Anoikis is a programmed cell death process that occurs when the contact between cells or the extracellular matrix is lost. We aim to identify the specific anoikis-related classifier genes for three ATLL subtypes, which could provide valuable insights into the molecular mechanisms underlying the disease's progression and potential targets for intervention. We conducted an analysis of differentially expressed anoikis genes (DEAGs) for identifying those associated with each subtype. Subsequently, we utilized multiclass support vector machine and logistic regression algorithms to recognize specific classifier anoikis-related genes distinguishing each ATLL subtype. The results revealed the activation of several cancer- and anoikis-related pathways. Moreover, specific potential biomarkers were pointed out for each ATLL subtype: acute, with S100A9 and MAOA; chronic, with IL10, CDH1, and CYP3A4; and smoldering with BCL2L1 and SNAI2. These anoikis-related genes play a role in regulating cell adhesion and survival signaling which are crucial for maintaining normal cellular homeostasis. The findings not only contribute to our understanding of ATLL progression but also offer potential targets for developing more effective therapeutic strategies and improving treatment outcomes for patients with different subtypes.
2025-06-23 | A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies.
Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4-directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220.
2024-12-19 | An HuR mutant, HuR-V225I, identified in adult T-cell Leukemia/Lymphoma, alters the pro-apoptotic function of HuR.
The RNA-binding protein HuR regulates various cellular processes, such as proliferation, differentiation, and cell fate. Moreover, recent studies have shown that HuR modulates the expression of factors important for tumor growth and progression. Despite its prominent role in tumorigenesis, until recently, there have been no reported mutations in HuR that have been associated to cancer. Here, we show that a HuR mutation, HuR-V225I, previously identified in a patient with Adult T-cell Leukemia/Lymphoma, interferes with the pro-apoptotic function of HuR. In response to apoptosis, HuR translocates to the cytoplasm and is cleaved in a caspase-dependent manner. In cervical cancer cells, neuroblastoma cells, and T-lymphocytes, we observed a decrease in cleavage of the HuR-V225I mutant under apoptotic conditions. This effect was shown to be mediated by the nuclear retention of HuR-V225I. Finally, expression of the HuR-V225I mutant decreases the cell's response to apoptotic stimuli through the increased expression of mRNAs encoding anti-apoptotic factors, such as XIAP and BCL-2. Therefore, our data establishes that the absence of HuR cytoplasmic translocation and cleavage promotes cell viability, and that acquiring this mutation during tumorigenesis may thus reduce the efficacy of cancer therapy.
cell therapies
2026-07-14 | Application Timing-Dependent Impact of Donor Source on Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is usually performed as a curative treatment for adult T-cell leukemia/lymphoma (ATL), following first-line chemotherapy. We conducted a nationwide retrospective study to examine the prognostic impact of donor sources based on transplantation application timings: human leukocyte antigen (HLA)-matched related donor (MRD; n = 253), unrelated donor (URD; n = 656), unrelated cord blood (U-CB; n = 599), and HLA-haploidentical related donor with post-transplant cyclophosphamide (PT-CY; n = 166). In patients with the early application of allo-HSCT (< 100 days from diagnosis), the multivariate analysis showed no significant difference in overall mortality (OM) among all donor sources. Regarding the middle timing of allo-HSCT (100-179 days), the U-CB group showed higher OM than the MRD group (hazard ratio [HR], 1.37; p = 0.013), while the URD and PT-CY groups showed no significant difference in OM with the MRD group. Concerning the late timing of allo-HSCT (180-270 days), the U-CB (HR, 1.88; p = 0.005) and PT-CY groups (HR, 1.90; p = 0.043) showed higher OM than the MRD group, whereas the URD group exhibited comparable OM to the MRD group. The present study demonstrated the differential impact of the graft source based on the timing of allo-HSCT for ATL; therefore, it is important to select an optimal alternative donor based on application timing.
2026-06-17 | Loss of HTLV-1-specific CD8+ T-cell immunity in virus carriers predisposed to adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATL) is caused by chronic infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 contains highly immunogenic CD8 + T-cell epitopes that elicit high frequencies of virus-specific CD8 + T cells in most virus carriers. Despite the virus being present in the tumor, HTLV-1-specific CD8 + cells are often undetectable in ATL. To characterize HTLV-1-specific CD8 + T cells during ATL development, we studied a subgroup of people living with asymptomatic HTLV-1 infection at very high risk of developing ATL. These so-called "high-risk" carriers have suspected premalignant lesions: expanded, HTLV-1-infected "ATL-like" clones circulating in their peripheral blood. Compared to viral antigen-burden matched controls, high-risk carriers had significantly fewer Tax-specific IFN-γ + CD8 + cells in peripheral blood. Furthermore, ex vivo CD8 + T cells from high-risk carriers did not efficiently kill autologous HTLV-1-infected T cells, including premalignant ATL-like clones. We stained Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells to test whether the low frequencies of functional CD8+ T cells resulted from phenotype or absolute frequency of HTLV-1-specific CD8 + T cells. High-risk carriers had significantly lower frequencies of Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells than controls, but we observed no difference in effector function, memory phenotype, or expression of checkpoint control molecules. In contrast, there was no difference in the frequency of CD8 + T cells specific for other viruses (cytomegalovirus, Epstein-Barr virus, influenza virus) between high-risk carriers and controls. This is the first report of HTLV-1-specific immune dysregulation in the premalignant stage of ATL. Low frequencies of HTLV-1-specific CD8 + T cells may contribute to ATL development and may be a novel therapeutic target for ATL prevention.
2026-06-16 | Improvements over time in survival after post-transplant relapse of adult T-cell leukaemia/lymphoma and trends of salvage therapy in a real-world experience.
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers potentially curative outcomes for adult T-cell leukaemia/lymphoma (ATL), but post-transplant refractory/relapsed (R/R) ATL is associated with poor outcomes. Advances have been made in transplant modalities, novel targeted agents and supportive care; however, it remains unclear whether these advances have improved survival outcomes of post-transplant R/R ATL. To clarify changes in survival after post-transplant R/R, we evaluated the survival outcomes in 1146 patients over a 24-year period, using a nationwide database. The period was divided into three groups: 1999-2010 (early period, as reference), 2011-2016 (middle period) and 2017-2022 (late period). In patients with refractory ATL, multivariate analyses showed no significant difference in overall mortality (OM) after post-transplant refractory in the early and middle periods, but a significantly lower OM in the late period than in the early period (hazard ratio [HR], 0.73 [95% confidence interval, 0.55-0.96]). In patients with relapsed ATL, OM after post-transplant relapse was significantly lower in the middle (HR 0.62 [0.48-0.80]) and late periods (HR 0.68 [0.52-0.90]) than in the early period. Thus, recent advances appear to have contributed to increased opportunities for therapeutic interventions, leading to improved survival outcomes in patients with post-transplant R/R ATL.
2026-05-04 | Development of Chimeric Antigen Receptor-Modified NK Cells for the Immunotherapy of Adult T-Cell Leukemia/Lymphoma.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy with a poor prognosis and limited therapeutic options. ATL cells exhibit aberrant surface glycosylation patterns resulting from dysregulated glycosyltransferase expression, representing a potentially tumor-specific therapeutic target. We previously isolated an ATL-specific single-chain variable fragment (scFv), S1TSCFR3-1, that selectively binds to ATL cell surface glycans. In this study, we engineered natural killer (NK) cells to express a chimeric antigen receptor (CAR) incorporating S1TSCFR3-1 and evaluated their therapeutic potential against ATL. In vitro, CAR-NK cells exhibited dose-dependent cytotoxicity against ATL cell lines, mediated primarily through enhanced granzyme B production, whereas no augmentation of cytotoxic activity was observed against non-ATL cell lines. S1TSCFR3-1 binding was detected in PBMCs from 3 of 7 ATL patients, and CAR-NK cells demonstrated significant cytotoxicity against PBMCs from a binding-positive patient. In a xenograft mouse model, administration of irradiated CAR-NK cells partially suppressed tumor burden as evidenced by reduced serum hsIL-2R levels, although survival benefit did not reach statistical significance. These findings suggest that CAR-NK cell therapy targeting ATL-associated aberrant glycan epitopes represents a potentially valuable therapeutic approach warranting further investigation.
2026-03-28 | How We Evaluate and Treat Leukemic Presentations of Mature T-Cell Lymphomas.
T-cell non-Hodgkin lymphomas, which arise from post-thymic mature T cells, constitute approximately 10-15% of all non-Hodgkin lymphomas. Their leukemic presentations, referred to here as mature T-cell leukemias, are relatively uncommon and present significant diagnostic and therapeutic challenges requiring an informed approach to diagnosis and management. The initial presentation is often persistent T-cell lymphocytosis that must be distinguished from reactive (non-malignant) causes. Unlike B-cell lymphocytosis, where clonality usually indicates malignancy, T-cell clonality can be detected in benign conditions such as autoimmune disorders and viral infections. Thus, establishing clonality is helpful but not sufficient, and a systematic diagnostic approach integrating clinical features, morphology, immunophenotype, and molecular findings is critical. This review outlines our approach to the diagnosis and treatment of four major subtypes of mature T-cell leukemias: T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), T-large granular lymphocytic leukemia (T-LGL), and Sézary syndrome (SS). Each section includes a discussion of clinical features, workup, and treatment options.
other
2026-06-04 | HTLV-1 Tax and HBZ cooperatively promote leukemogenesis through miR-155-mediated PTEN suppression and PI3K-Akt activation.
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), but the full scope of its oncogenic mechanisms remains elusive. While the viral oncoprotein Tax drives early oncogenesis, its expression is frequently silenced in later stages of ATLL, whereas the HTLV-1 basic leucine zipper factor (HBZ) is constitutively expressed throughout infection. This shifting viral expression profile underscores the critical need to define HBZ-specific oncogenic mechanisms. Here, we identify miR-155 as a key oncogenic driver in ATLL and reveal a novel, HBZ-dependent post-transcriptional regulatory axis that sustains its overexpression. We confirm Tax-mediated transcriptional activation of miR-155 but further demonstrate that HBZ enhances miR-155 maturation by elevating Dicer expression and promoting its processing of pre-miR-155. The elevated miR-155 promotes tumorigenesis through targeting PTEN and activating PI3K-Akt pathway. Functional studies demonstrate that miR-155 overexpression drives ATLL progression by enhancing proliferation and inhibiting apoptosis, while its inhibition reverses these malignant phenotypes. Xenograft models confirm that miR-155 blockade significantly reduces tumor growth. Our results uncover a cooperative mechanism by which HTLV-1 Tax and HBZ jointly drive miR-155 overexpression to promote leukemogenesis and identify miR-155 as a potential therapeutic target in ATLL. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive cancer caused by HTLV-1 with limited treatment options. We show that HTLV-1 hijacks the host microRNA miR-155 to drive tumor growth. While the viral protein Tax activates miR-155 transcription, we discovered that HBZ-constitutively expressed even when Tax is silenced-sustains miR-155 expression by upregulating Dicer and enhancing miR-155 processing. Elevated miR-155 then suppresses PTEN and activates the PI3K-Akt pathway, promoting cancer cell proliferation. Importantly, blocking miR-155 significantly reduces tumor growth in mouse models, identifying miR-155 as a promising therapeutic target for ATLL.
2026-06-01 | Human T-Lymphotropic Virus Type 1 (HTLV-1): Molecular Markers, Immunopathogenesis and Future Perspectives for Vaccine Development and Immunotherapy in Adult T-Cell Leukemia/ Lymphoma
Background: Human T-lymphotropic virus type 1 (HTLV-1) is a complex oncogenic delta-retrovirus and the causative agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).Infecting an estimated 5-10 million individuals globally, the virus exerts its oncogenic potential through two pivotal regulatory proteins: Tax and the HTLV-1 basic leucine zipper factor (HBZ), which orchestrate a cascade of molecular events including NF-κB activation, epigenetic reprogramming, immune evasion and clonal T-cell expansion.Despite decades of research, no prophylactic or therapeutic vaccine has received clinical approval.Objectives: This review comprehensively synthesizes current knowledge on HTLV-1 molecular pathogenesis, key molecular biomarkers, HLA-restriction of immune responses and emerging vaccine strategies including peptide-based, DNA-based, mRNA-based, viral vector and dendritic cell-based platforms.It further explores the therapeutic landscape of ATLL including mogamulizumab (anti-CCR4), CAR-T cell therapy and checkpoint inhibitors. Methods:A systematic narrative review of literature from PubMed, Scopus and Web of Science was performed, incorporating 50 peer-reviewed references spanning foundational discoveries to recent clinical trials as of 2024. Conclusion:The molecular complexity of HTLV-1 -particularly the dichotomous roles of Tax and HBZ, HLA-restricted CTL immunodominance and proviral load as a prognostic biomarker -offers multiple actionable targets for next-generation vaccine and immunotherapy design.Integrating multi-epitope mRNA platforms, HBZ-directed CTL induction and combination immunotherapy holds transformative promise for this neglected yet lethal retroviral malignancy.
2026-05-06 | Design and in silico evaluation of an mRNA vaccine against HTLV-1 using AI-driven reverse vaccinology approaches.
Human T-lymphotropic virus type 1 (HTLV-1) is the first discovered human oncogenic retrovirus that can cause adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis, and several other diseases. Due to the poor prognosis of these diseases and the limited therapeutic modalities, the need for an HTLV-1 vaccine is crucial. The current study has used an artificial intelligence-driven reverse vaccinology approach to design an mRNA vaccine against HTLV-1. The two most antigenic proteins of the virus were selected and analyzed using multiple immunoinformatics tools to identify the antigenic immunodominant epitopes for T- and B-cells. Subsequently, the final selected epitopes and the adjuvant were connected using proper linkers. Subsequently, multiple 3D structures were modeled for the vaccine. After refining and evaluating the modeled structures, the best model was selected as the final candidate vaccine structure. The proposed mRNA structure is a potential vaccine with suitable immunological and physicochemical properties against HTLV-1. Docking and simulation analyses showed a proper interaction between the vaccine and the corresponding receptor of the employed adjuvant. However, additional experimental studies are required to further confirm the vaccine's efficacy.
2026-02-05 | Suppressor of cytokine signaling (SOCS) proteins in human retroviral infections.
Retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) have evolved sophisticated mechanisms to establish persistent infection by manipulating host immune signaling networks. A central target of this viral interference is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which governs cytokine-, interferon-, and growth factor–mediated immune responses. Tight control of this pathway is mediated by the suppressor of cytokine signaling (SOCS) protein family, comprising eight members (SOCS1–SOCS7 and cytokine-inducible SH2-containing protein, CIS) that function as inducible negative feedback regulators of JAK activity and cytokine receptor signaling. Accumulating evidence indicates that HIV-1 and HTLV-1 exploit SOCS proteins most prominently SOCS1 and SOCS3 to dampen antiviral interferon signaling, inhibit STAT activation, impair antigen presentation, and promote viral persistence. In HTLV-1 infection, dysregulation of SOCS expression further contributes to the survival, proliferation, and immune evasion of infected T cells, implicating SOCS pathways in the pathogenesis of adult T-cell leukemia/lymphoma. Despite these insights, the majority of studies have focused narrowly on SOCS1 and SOCS3, leaving the roles of other SOCS family members largely unexplored. This mini-review summarizes current knowledge on SOCS-mediated modulation of JAK/STAT signaling in HIV-1 and HTLV-1 infections, identifies critical gaps in our understanding of SOCS family diversity in retroviral immune evasion, and discusses the therapeutic potential of targeting SOCS pathways to restore antiviral immunity and limit retrovirus-associated disease.
2025-12-09 | Intra-pol proviral open region of HTLV-1 controls the transcription from both long terminal repeats.
Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+ T lymphocytes and causes both malignant and inflammatory diseases: the aggressive malignancy known as Adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory syndromes. HTLV-1 infection is established by integration of proviral DNA (~9000 bp) into the host genome. In HTLV-1, two viral genes, tax and HBZ, play critical roles in viral transcription and promotion of T-cell proliferation, respectively. The present study was undertaken to test the hypothesis that the higher-order structure of proviral chromatin regulates its transcription on both the plus strand and the minus strand. ATAC-seq analysis identified an open chromatin region in the pol gene of proviral DNA, which we name IPOR, in many ATL cases. Using reporter assays, it was found that the sequence of IPOR suppresses the transcription of the plus strand and activates that of the minus strand. Binding motifs of Eomes and TEAD proteins were predicted in this region, and we confirmed recruitment of the transcription factors to their respective motifs by ChIP-qPCR. A mutant of IPOR which cannot bind the transcription factors weakened the transcriptional activating effects compared with the wild type, suggesting that the IPOR and those transcription factors suppress the 5' long terminal repeat (LTR) but activate the 3'LTR. In addition, a mutant HTLV-1 molecular clone, which possesses the IPOR mutant, produced a higher titer of virus than the wild type. RNA-seq analysis of HTLV-1-infected cell lines, in which Tax expression can be traced after induction, revealed that EOMES expression decreases during the tax transcriptional burst and resumes following termination of the burst. These findings suggested that the expression dynamics of Eomes affect the transient expression of Tax. The IPOR sequence appears to regulate the transcription from both LTRs, suppressing the 5'LTR but activating the 3'LTR. Recruitment of Eomes to the IPOR is likely to influence the expression of Tax and HBZ. Since both viral genes are involved in diverse mechanisms for viral replication, cellular proliferation, and immune regulation, the IPOR may play a role in fine-tuning the modes of viral persistence in vivo.
small molecules
2026-09-26 | Replication Stress Tolerance in Adult T-Cell Leukemia.
Replication stress (RS) represents a major vulnerability of cancer cells treated with nucleoside analogs and related antimetabolites; however, tumors frequently acquire tolerance mechanisms that permit survival despite persistent DNA lesions. This review examines molecular determinants of RS tolerance, focusing on human T-cell leukemia virus type 1 (HTLV-1)-mediated adult T-cell leukemia/lymphoma (ATL) as a model of virus-mediated rewiring of DNA damage responses. Chain-terminating nucleoside analogs generate aberrant replication intermediates, including blocked 3' DNA termini, mis-incorporated bases, and stalled replication forks. In ATL, viral oncoproteins suppress key components of replication stress response pathways, notably tyrosyl-DNA phosphodiesterase 1 (TDP1) and mismatch repair (MMR), thereby creating exploitable repair deficiencies. Consistent with this vulnerability, ATL cells exhibit marked sensitivity to replication stress-inducing agents such as irinotecan (CPT-11) and the chain-terminating nucleoside analog abacavir. Recent CRISPR-based functional genomics studies further identify Schlafen 11 (SLFN11) as an independent and dominant regulator of RS sensitivity. SLFN11 determines the fate of stressed replication forks independently of lesion processing, acting as an execution factor that converts otherwise tolerable RS into irreversible replication arrest. We conclude by discussing therapeutic strategies that exploit RS tolerance defects in ATL, including biomarker-guided nucleoside analog therapy, and rational combination approaches targeting compensatory RS pathways.
2026-09-23 | Durable immunovirological control after sequential mogamulizumab and tucidinostat in relapsed or refractory adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive HTLV-1-associated T-cell neoplasm, and durable control of relapsed/refractory disease remains difficult without allogeneic hematopoietic stem cell transplantation. Mogamulizumab, an afucosylated anti-C-C chemokine receptor type 4 (CCR4) monoclonal antibody, and tucidinostat, an oral histone deacetylase inhibitor, have activity in this setting, but the immunovirological consequences of sequential CCR4-directed therapy and epigenetic modulation are unclear. We describe two patients with relapsed or refractory ATLL who achieved prolonged disease control after mogamulizumab/tucidinostat-based sequential therapy and underwent longitudinal monitoring of Tax301-309-specific CD8+ T cells, CD4/CD8 dynamics, HTLV-1 proviral DNA, and T-cell receptor (TCR) Vβ repertoire. Patient 1 had lymphoma-type ATLL with metabolic partial response after mogamulizumab plus EPOCH; tucidinostat was initiated 63 days after the final mogamulizumab dose. Tax301-309-specific CD8+ T cells increased from 0.03% at tucidinostat initiation to >0.8% during long-term follow-up, and disease control persisted for 32 months after tucidinostat initiation. Patient 2 had multiply relapsed ATLL and received four cycles of sequential mogamulizumab/tucidinostat, followed by rapid disappearance of circulating ATLL cells, normalization of soluble interleukin-2 receptor, and marked reduction of HTLV-1 proviral load from 565.7 copies/1,000 peripheral blood mononuclear cells to low levels. Disease control persisted for 17 months after treatment discontinuation. In both patients, TCR Vβ repertoire analysis showed memory CD8+ T-cell-predominant patterns, including expansion of a Vβ2 memory CD8+ T-cell population. These observations are hypothesis-generating and suggest that sequential tumor debulking, CCR4/Treg-axis modulation, and epigenetic treatment may create a context permissive for HTLV-1 antigen-specific cellular immune surveillance in selected patients with ATLL.
2026-09-10 | Outcomes of CHOP versus CHOEP/EPOCH in aggressive adult T-cell leukemia/lymphoma: an international cohort analysis.
Aggressive adult T-cell leukemia/lymphoma (ATL) subtypes (i.e., acute and lymphomatous) are rare diseases, and the conventional management with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has historically yielded poor outcomes. The benefit of etoposide-containing regimens (CHOEP/EPOCH) in the first-line setting is inconclusive. We compared the effectiveness of CHOEP/EPOCH versus CHOP in aggressive ATL. We conducted an international, multicenter retrospective cohort study among newly diagnosed patients with ATL during 2000-2023 across five Latin American countries and the United States. Study endpoints included overall response rate (ORR) and overall survival (OS). Propensity score weighting was used to balance the treatment groups, and findings are reported for each ATL subtype. Among 328 patients, 108 had acute ATL and 220 had lymphomatous ATL. In weighted analyses, CHOEP/EPOCH was not statistically associated with a higher ORR compared to CHOP in lymphomatous ATL (66% vs. 58%; Odds ratio [OR]=2.08, 95% confidence interval [CI]=0.76-5.75) or acute ATL (42% vs. 58%; OR=0.68, 95% CI=0.06-7.84). With a median follow-up of 34 months (interquartile range [IQR] 15-73) in lymphomatous ATL, CHOEP/EPOCH was associated with a higher 3-year OS (34% vs. 12%; HR=0.55, 95% CI=0.35-0.87). However, with a median follow-up of 63 months (IQR 16-110) in acute ATL, CHOEP/EPOCH was not associated with improved 3-year OS (8% vs. 11%; HR=0.95, 95% CI=0.51-1.77). In conclusion, CHOEP/EPOCH may be associated with improved survival in lymphomatous ATL, while results in acute ATL were inconclusive. These findings support the need for prospective interventional studies to validate the subtype-specific benefits.
2026-09-08 | HHV-6 Encephalitis Presenting With Severe SIADH and CO₂ Narcosis in Non-Transplant Smoldering Adult T-Cell Leukemia/Lymphoma
Objective:Rare coexistence of disease or pathology Background:Human herpesvirus 6 (HHV-6) encephalitis is best recognized after allogeneic hematopoietic stem cell transplantation but can also occur in non-transplant immunocompromised patients.Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) may precede or accompany HHV-6 encephalitis.Severe SIADH as an early dominant clue in non-transplant patients with smoldering adult T-cell leukemia/lymphoma (ATLL) is not fully described. Case Report:A 55-year-old woman with smoldering ATLL received systemic corticosteroid therapy for clinically diagnosed human T-cell leukemia virus type 1 (HTLV-1)-associated uveitis and was admitted for progressive pulmonary infection.Bronchoscopic specimens revealed polymicrobial infection, including Nocardia and Actinomyces; invasive pulmonary aspergillosis was also clinically suspected.Although pulmonary findings improved with antimicrobial and antifungal therapy, she developed nausea, acute impairment of consciousness, and severe SIADH-associated hyponatremia.Serum sodium decreased to 113 mmol/L, and consciousness did not adequately improve after sodium correction.Cerebrospinal fluid obtained by lumbar puncture on hospital day 13 showed HHV-6 DNA positivity (1.0 × 10 3 copies/mL).Brain magnetic resonance imaging demonstrated bilateral cortical and limbic abnormalities, supporting a clinical diagnosis of HHV-6 encephalitis.Ganciclovir was initiated on hospital day 15 along with sodium correction, tolvaptan, and supportive care.The patient subsequently developed hypercapnic respiratory failure and CO 2 narcosis requiring mechanical ventilation.Her neurologic and respiratory status gradually improved, and she was discharged on hospital day 53. Conclusions:In non-transplant patients with ATLL, corticosteroid exposure, and opportunistic infection, severe SIADH accompanied by new neurologic symptoms can be an early clue to HHV-6 encephalitis.Early recognition and prompt initiation of antiviral therapy may help to improve neurologic outcomes.
2026-08-13 | Rewiring of the Apoptotic Rheostat in HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of apoptotic pathways, which is a key determinant of long-term viral persistence and favors malignant transformation. This review describes the mechanisms through which HTLV-1 gene products, including Tax and HBZ, reprogram host-cell signaling controlling the "apoptotic rheostat", an integrated network connecting redox metabolism, and response to apoptotic cues and immune pressure. We also highlight emerging therapeutic strategies to restore sensitivity to apoptosis, including BH3-mimetic drugs and rational combination approaches. Deciphering how HTLV-1 reconfigures the apoptotic network provides a conceptual and therapeutic framework for targeting death pathway vulnerabilities in ATLL and potentially other hematological neoplasms.
antibodies
2026-05-01 | C51-15 Refractory, Pthrp-independent Hypercalcemic Crisis Unmasking Htlv-1-associated Adult T-cell Leukemia/lymphoma With Diffuse Osteolysis
Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL), driven by HTLV-1, frequently presents with hypercalcemia, often attributed to PTHrP; however, RANKL/cytokine-mediated osteoclast activation can cause PTHrP-independent hypercalcemia that is refractory to standard therapy. Case Presentation A 49-year-old woman (BMI 45.7; prior sleeve gastrectomy) presented with lethargy, weakness, dyspnea, and severe hypercalcemia (total Ca 19.7 mg/dL). The patient also had a similar admission in another hospital for hypercalcemia. Hypercalcemia recurred despite aggressive IV fluids, repeated calcitonin, and zoledronic acid. PTH and PTHrP were suppressed; vitamin D was low. Imaging showed bilateral axillary/pelvic/inguinal lymphadenopathy and diffuse osteolytic vertebral lesions. Peripheral blood flow cytometry revealed an aberrant CD4+/CD7−/CD5− T-cell population (19% of leukocytes) with HTLV-1 seropositivity, supporting ATLL. Bone marrow was markedly hypocellular; FISH for common myeloid/lymphoid neoplasia was negative. Hospitalization was notable for transient thrombocytopenia, morbilliform rash responsive to topical steroids/antihistamines, prerenal AKI resolving with fluids, and electrolyte losses (K/Mg/Phos) requiring repletion. She remained hemodynamically stable on room air with persistent sinus tachycardia. Given refractory hypercalcemia and new ATLL diagnosis, she was transferred to a tertiary center for chemotherapy ± stem-cell transplant. Discussion ATLL-associated hypercalcemia may occur despite suppressed PTHrP, via RANKL-dependent osteoclastogenesis driven by HTLV-1/Tax signaling; diffuse osteolysis can accompany this physiology. Recognition of PTH/PTHrP-independent hypercalcemia is crucial when standard therapy fails. In bisphosphonate-refractory cases, denosumab (RANKL blockade) is an evidence-supported next step but risks prolonged hypocalcemia, necessitating careful ICU/step-down monitoring and calcium/vitamin D repletion strategies. This case emphasizes a diagnostic/therapeutic framework for severe recurrent hypercalcemia with lymphadenopathy and bone lesions culminating in ATLL. Conclusion Refractory hypercalcemia with suppressed PTH/PTHrP should prompt evaluation for HTLV-1-related ATLL and RANKL-mediated osteolysis. Early multidisciplinary management and consideration of denosumab may be lifesaving. This abstract is funded by: None
2025-10-30 | Pathobiological link between CD30 and abnormal lymphocytes in adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is a T-cell malignancy with poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is characterized by the emergence of abnormal lymphocytes, represented by the so called "flower cell". However, the mechanisms by which these cells contribute to tumorigenic processes associated with HTLV-1 infection are not well understood. Recent reports have suggested that CD30, tumor necrosis factor receptor superfamily 8 plays a role in the generation of these abnormal lymphocytes, providing insight into the involvement of CD30 in the tumorigenic process of HTLV-1-infected cells. Since CD30 can be targeted with brentuximab vedotin (BV), an anti-CD30 antibody linked with monomethyl auristatin E, a tubulin toxin, it is essential to gain a deeper understanding of the functions of CD30 in HTLV-1-infected cells in order to develop effective strategies for treating and preventing ATLL. This review describes the current understanding of how CD30 impacts the development of ATLL in cells infected with HTLV-1, with a specific emphasis on the connection between CD30 and the generation of abnormal lymphocytes.
2025-10-21 | A Multicenter Real-World Retrospective Study for Brentuximab Vedotin, Cyclophosphamide, Doxorubicin, and Prednisolone for Previously Untreated Patients With CD30-Positive Adult T-Cell Leukemia-Lymphoma.
Adult T-cell leukemia-lymphoma (ATL) is a rare, aggressive malignancy prevalent in Japan, the Caribbean, and Central/South America. This multicenter retrospective study evaluated the effectiveness and safety of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisolone (BV-CHP) in patients aged ≥ 18 years with previously untreated CD30-positive ATL, verified through immunohistochemistry/flow cytometry, from six hospitals in Japan. Outcomes included overall response rate (ORR; primary outcome), overall survival (OS), progression-free survival (PFS), complete response rate (CRR), disease control rate (DCR), and safety. Subgroup analyses evaluated lesion site, ATL subtype, age, and CD30 expression. Of 46 screened patients, 36 (median age 71 years; 66.7% female) were analyzed and started BV-CHP between April 2020 and January 2024. CD30 positivity was confirmed in all patients. ORR was 86.1% (95% confidence interval [CI] 70.5-95.3), CRR 61.1% (95% CI 43.5-76.9), and DCR 91.7% (95% CI 77.5-98.3). ORR by lesion site (lymph nodes, peripheral blood, skin) was 93.8%, 90.9%, and 83.3%, respectively, by ATL subtype (acute, lymphoma) was 78.9% and 94.1%, respectively, and by age (≤ 70 years, > 70 years) was 84.6% and 87.0%, respectively. One patient with CD30 expression < 10% achieved a complete response; ORR was 73.7% in 19 patients with CD30 expression ≥ 10%. Median OS and PFS was 535 days (95% CI 343-not estimable) and 205 days (95% CI 166-279), respectively. Treatment-emergent adverse events of any grade and grade ≥ 3 both occurred in 88.9% of patients, with neutropenia, febrile neutropenia, and thrombocytopenia being most common. Among 11 patients who underwent allogeneic stem cell transplantation, two developed acute graft-versus-host disease; median PFS was 234 days (95% CI 168-343), compared with 180 days (95% CI 96-279) without transplantation. BV-CHP demonstrated high ORR and CRR across age groups and ATL subtypes with a manageable safety profile, supporting its potential use as a standard treatment option.
2025-09-17 | Extracellular CD30 Regulates Brentuximab Vedotin-Induced Cell Death in an Adult T-Cell Leukemia Cell Line.
Adult T-cell leukemia/lymphoma (ATL) is a malignant tumor of mature T lymphocytes induced by human T-cell leukemia virus 1, and it has a poor prognosis. Brentuximab vedotin (BV) is included in the treatment of CD30-positive ATL, but there are no predictive biomarkers for the treatment effects of BV. Serum soluble CD30 (sCD30) concentrations are increased in aggressive ATL at the time of diagnosis, but the effect of extracellular CD30 on BV-induced cell death in ATL is unknown. Similarly, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 possess CD30 sheddase activity in anaplastic large cell lymphoma, but this activity is unclear in ATL. In this study, we showed that sCD30 concentrations were associated with BV activity in ATL-associated cell lines. Extracellular vesicles, such as exosomes containing CD30, also inhibited BV activity. Furthermore, knockdown of ADAM10/17 significantly reduced sCD30 concentrations and increased BV-induced cell death. These results suggest that ADAM10 and ADAM17 are involved in sCD30 production in ATL. Furthermore, endogenous extracellular CD30, such as sCD30 and CD30-positive extracellular vesicles shed by ADAM10/17, may be involved in BV-induced cell death. Taken together, our findings suggest that extracellular CD30 concentrations, including CD30 on extracellular vesicles, are a useful biomarker for BV therapy in ATL.
2025-08-21 | Development of a silicon phthalocyanine analogue for near-infrared photoimmunotherapy and its application to HTLV-1-infected leukemic cells.
Near-infrared photoimmunotherapy (NIR-PIT) employing an antibody labeled with a silicon phthalocyanine dye, IR700, was approved as a minimally invasive treatment for unresectable recurrent head and neck cancer in Japan in 2020. However, further derivatization of IR700 is needed to increase the efficiency of cancer treatment. Here, we developed SiPc-1 as an IR700 analog, in which the linker was constructed using click chemistry to simplify the synthetic scheme and its position was switched from α to β on the benzene ring of phthalocyanine to eliminate intramolecular steric repulsion. We evaluated the cleavage rate of the water-soluble axial moieties of SiPc-1 upon photoirradiation, the cytotoxicity, and the morphological change (blebbing) of treated cells upon photoirradiation. We performed gene expression and protein expression analyses to find a target antigen selectively expressed on cells infected with human T-cell lymphotropic virus type 1 (HTLV-1), the causative virus of adult T-cell leukemia/lymphoma (ATL), and identified CD25 as a suitable target antigen. An anti-CD25 antibody, basiliximab, labeled with SiPc-1 (bas-SiPc-1) showed selective toxicity towards HTLV-1-infected cultured cells and ATL patients' peripheral blood mononuclear cells upon photoirradiation.
proteins
2026-06-12 | Kunxian Capsule Exerts Antitumor Effects by Activating the IL-17 Signaling Pathway to Inhibit the Proliferation, Apoptosis, Cell Cycle, and Induce Reactive Oxygen Species Production in C8166 Tumor Cells.
Kunxian capsule (KXJN), a patented traditional Chinese medicine used for autoimmune diseases, remains unexplored in oncology. This study investigated its potential antitumor effects against adult T-cell leukemia/lymphoma (A-ATL). Network pharmacology identified KXJN-related targets from TCMSP and UniProt, and A-ATLassociated DEGs from GEO. Candidate targets and pathways were analyzed via Microbiotics and String. In vitro validation used C8166 cells, assessing proliferation (MTT assay), apoptosis, cell cycle, ROS production (flow cytometry), and protein/mRNA expression (Western blot, RT-qPCR). A total of 106 potential targets of KXJN were identified against A-ATL, with core nodes (JUN, IL-6, TNF) linked to the IL-17 pathway and other pathways. KXJN dose- and time-dependently inhibited C8166 proliferation, promoted apoptosis, and increased ROS. It activated the IL-17 pathway, upregulating associated proteins (ACT1, IL-17RA, TRAF6), core targets (JUN, IL-6, TNF), and cytokines (CXCL1, CXCL2, CCL20). KXJN exerts antitumor effects on C8166 cells by suppressing proliferation, inducing apoptosis and ROS, activating IL-17 signaling, and modulating cell cycle progression. These findings highlight KXJN's potential in tumor therapy, though further in vitro and in vivo studies are required to elucidate its precise mechanisms.
2025-11-03 | Characterizing the biological function FOXO3 and its role as a predictive biomarker in HTLV-1 related adult T-cell leukemia-lymphoma
Abstract Adult T-cell leukemia-lymphoma (ATL) is a highly aggressive T cell malignancy with dismal prognosis caused by the human T-cell leukemia virus, type 1 (HTLV-1), which is prevalent in Japan, South America, and the Caribbean. Because of our geographic proximity to HTLV-1 endemic regions, ATL patients are commonly encountered in south Florida and northeast U.S.A. At least four clinical ATL subtypes have been recognized. The acute and lymphomatous lethal forms are by far the most common variants. The 4-year survival rates for lymphomatous and acute type ATL are less than 20%, with median survival less than 11 months. First-line treatment options include multi-agent cytotoxic chemotherapy and interferon-a (IFNa)-based therapy. We recently published a large genomic study of ATL found in the Western hemisphere (W-ATLL) and discovered mutational patterns that differed from Japanese patients [Myers and Choi group, Gru, and Ramos et al. Haematologica. 2024 Dec 1;109(12):4021-4039]. A notorious finding was the recurrence of novel FOXO3 mutations (R177W and D199N) mapping to the DNA binding domain in 10% of patients (17% of African-descent cases) with acute type ATL suggesting that the possible tumor suppressive function of FOXO3 in ATL requires DNA binding. In total, FOXO3 mutations or genomic deletions occurred at a frequency of ~20%. FOXO3 is a transcriptional activator, whose function is known to induce the expression of pro-apoptotic genes (i.e., BIM and FasL) and to promote drug-induced autophagy. FOXO3 protein has been demonstrated to be inactivated by phosphorylation via AKT and targeted by HTLV-1 bZip (HBZ) protein, which sequesters it in the nucleus while attenuating its pro-apoptotic function. W-ATL tumors analyzed from our cohort generally showed reduced FOXO3 protein expression, suggesting that dysregulated FOXO3 function could be an important oncogenic event in ATL development. Our preliminary in vitro studies using our patient derived ATL cell lines showed that overexpression of FOXO3 increased antineoplastic drug-induced apoptosis in ATL cells, while overexpression of R177W and D199N mutant forms and FOXO3 knock-out (KO) conferred resistance to anti-neoplastic drugs. More recently, our ATL cell lines were engineered to overexpress FOXO3 via more efficient transduction of tetracycline-inducible pRetroX vectors demonstrating FOXO3 slow the proliferation of ATL cells in vitro. We also correlated our published exome sequencing with patient outcomes (treatment response rates and survival) using our existing well-annotated database. Surprisingly, W-ATLL patients carrying mutated FOXO3 responded better to IFNa-based therapies after achieving a significantly higher complete response rate (37% vs. 16%) and longer progression-free survival (7 months vs. 0.9 months, p= 0.0172) (unpublished data). Thus, FOXO3 mutations may result in ATL forms that are perhaps more susceptible to immune-based therapies such as IFN which depend less on direct drug-induced apoptosis. Our current studies aim to confirm and define the functional role of FOXO3 in ATL and to evaluate the clinical implications of altered FOXO3 in this disease. Given our preliminary findings, we are investigating FOXO3 as a predictive biomarker in prospective ATL samples and characterizing its functional using our preclinical models.
2025-08-27 | MultiClass Machine Learning-based Identification of Anoikis-related Genes Across Three Adult T-cell Leukemia/Lymphoma Subtypes
Abstract Adult T-cell leukemia/lymphoma (ATLL) is a type of cancer that originates from T-cells infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Anoikis is a programmed cell death process that occurs when the contact between cells or the extracellular matrix is lost. We aim to identify the specific anoikis-related classifier genes for three ATLL subtypes, which could provide valuable insights into the molecular mechanisms underlying the disease's progression and potential targets for intervention. We conducted an analysis of differentially expressed anoikis genes (DEAGs) for identifying those associated with each subtype. Subsequently, we utilized multiclass support vector machine and logistic regression algorithms to recognize specific classifier anoikis-related genes distinguishing each ATLL subtype. The results revealed the activation of several cancer- and anoikis-related pathways. Moreover, specific potential biomarkers were pointed out for each ATLL subtype: acute, with S100A9 and MAOA; chronic, with IL10, CDH1, and CYP3A4; and smoldering with BCL2L1 and SNAI2. These anoikis-related genes play a role in regulating cell adhesion and survival signaling which are crucial for maintaining normal cellular homeostasis. The findings not only contribute to our understanding of ATLL progression but also offer potential targets for developing more effective therapeutic strategies and improving treatment outcomes for patients with different subtypes.
2025-06-23 | A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies.
Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4-directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220.
2024-12-19 | An HuR mutant, HuR-V225I, identified in adult T-cell Leukemia/Lymphoma, alters the pro-apoptotic function of HuR.
The RNA-binding protein HuR regulates various cellular processes, such as proliferation, differentiation, and cell fate. Moreover, recent studies have shown that HuR modulates the expression of factors important for tumor growth and progression. Despite its prominent role in tumorigenesis, until recently, there have been no reported mutations in HuR that have been associated to cancer. Here, we show that a HuR mutation, HuR-V225I, previously identified in a patient with Adult T-cell Leukemia/Lymphoma, interferes with the pro-apoptotic function of HuR. In response to apoptosis, HuR translocates to the cytoplasm and is cleaved in a caspase-dependent manner. In cervical cancer cells, neuroblastoma cells, and T-lymphocytes, we observed a decrease in cleavage of the HuR-V225I mutant under apoptotic conditions. This effect was shown to be mediated by the nuclear retention of HuR-V225I. Finally, expression of the HuR-V225I mutant decreases the cell's response to apoptotic stimuli through the increased expression of mRNAs encoding anti-apoptotic factors, such as XIAP and BCL-2. Therefore, our data establishes that the absence of HuR cytoplasmic translocation and cleavage promotes cell viability, and that acquiring this mutation during tumorigenesis may thus reduce the efficacy of cancer therapy.
cell therapies
2026-07-14 | Application Timing-Dependent Impact of Donor Source on Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is usually performed as a curative treatment for adult T-cell leukemia/lymphoma (ATL), following first-line chemotherapy. We conducted a nationwide retrospective study to examine the prognostic impact of donor sources based on transplantation application timings: human leukocyte antigen (HLA)-matched related donor (MRD; n = 253), unrelated donor (URD; n = 656), unrelated cord blood (U-CB; n = 599), and HLA-haploidentical related donor with post-transplant cyclophosphamide (PT-CY; n = 166). In patients with the early application of allo-HSCT (< 100 days from diagnosis), the multivariate analysis showed no significant difference in overall mortality (OM) among all donor sources. Regarding the middle timing of allo-HSCT (100-179 days), the U-CB group showed higher OM than the MRD group (hazard ratio [HR], 1.37; p = 0.013), while the URD and PT-CY groups showed no significant difference in OM with the MRD group. Concerning the late timing of allo-HSCT (180-270 days), the U-CB (HR, 1.88; p = 0.005) and PT-CY groups (HR, 1.90; p = 0.043) showed higher OM than the MRD group, whereas the URD group exhibited comparable OM to the MRD group. The present study demonstrated the differential impact of the graft source based on the timing of allo-HSCT for ATL; therefore, it is important to select an optimal alternative donor based on application timing.
2026-06-17 | Loss of HTLV-1-specific CD8+ T-cell immunity in virus carriers predisposed to adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATL) is caused by chronic infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 contains highly immunogenic CD8 + T-cell epitopes that elicit high frequencies of virus-specific CD8 + T cells in most virus carriers. Despite the virus being present in the tumor, HTLV-1-specific CD8 + cells are often undetectable in ATL. To characterize HTLV-1-specific CD8 + T cells during ATL development, we studied a subgroup of people living with asymptomatic HTLV-1 infection at very high risk of developing ATL. These so-called "high-risk" carriers have suspected premalignant lesions: expanded, HTLV-1-infected "ATL-like" clones circulating in their peripheral blood. Compared to viral antigen-burden matched controls, high-risk carriers had significantly fewer Tax-specific IFN-γ + CD8 + cells in peripheral blood. Furthermore, ex vivo CD8 + T cells from high-risk carriers did not efficiently kill autologous HTLV-1-infected T cells, including premalignant ATL-like clones. We stained Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells to test whether the low frequencies of functional CD8+ T cells resulted from phenotype or absolute frequency of HTLV-1-specific CD8 + T cells. High-risk carriers had significantly lower frequencies of Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells than controls, but we observed no difference in effector function, memory phenotype, or expression of checkpoint control molecules. In contrast, there was no difference in the frequency of CD8 + T cells specific for other viruses (cytomegalovirus, Epstein-Barr virus, influenza virus) between high-risk carriers and controls. This is the first report of HTLV-1-specific immune dysregulation in the premalignant stage of ATL. Low frequencies of HTLV-1-specific CD8 + T cells may contribute to ATL development and may be a novel therapeutic target for ATL prevention.
2026-06-16 | Improvements over time in survival after post-transplant relapse of adult T-cell leukaemia/lymphoma and trends of salvage therapy in a real-world experience.
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers potentially curative outcomes for adult T-cell leukaemia/lymphoma (ATL), but post-transplant refractory/relapsed (R/R) ATL is associated with poor outcomes. Advances have been made in transplant modalities, novel targeted agents and supportive care; however, it remains unclear whether these advances have improved survival outcomes of post-transplant R/R ATL. To clarify changes in survival after post-transplant R/R, we evaluated the survival outcomes in 1146 patients over a 24-year period, using a nationwide database. The period was divided into three groups: 1999-2010 (early period, as reference), 2011-2016 (middle period) and 2017-2022 (late period). In patients with refractory ATL, multivariate analyses showed no significant difference in overall mortality (OM) after post-transplant refractory in the early and middle periods, but a significantly lower OM in the late period than in the early period (hazard ratio [HR], 0.73 [95% confidence interval, 0.55-0.96]). In patients with relapsed ATL, OM after post-transplant relapse was significantly lower in the middle (HR 0.62 [0.48-0.80]) and late periods (HR 0.68 [0.52-0.90]) than in the early period. Thus, recent advances appear to have contributed to increased opportunities for therapeutic interventions, leading to improved survival outcomes in patients with post-transplant R/R ATL.
2026-05-04 | Development of Chimeric Antigen Receptor-Modified NK Cells for the Immunotherapy of Adult T-Cell Leukemia/Lymphoma.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy with a poor prognosis and limited therapeutic options. ATL cells exhibit aberrant surface glycosylation patterns resulting from dysregulated glycosyltransferase expression, representing a potentially tumor-specific therapeutic target. We previously isolated an ATL-specific single-chain variable fragment (scFv), S1TSCFR3-1, that selectively binds to ATL cell surface glycans. In this study, we engineered natural killer (NK) cells to express a chimeric antigen receptor (CAR) incorporating S1TSCFR3-1 and evaluated their therapeutic potential against ATL. In vitro, CAR-NK cells exhibited dose-dependent cytotoxicity against ATL cell lines, mediated primarily through enhanced granzyme B production, whereas no augmentation of cytotoxic activity was observed against non-ATL cell lines. S1TSCFR3-1 binding was detected in PBMCs from 3 of 7 ATL patients, and CAR-NK cells demonstrated significant cytotoxicity against PBMCs from a binding-positive patient. In a xenograft mouse model, administration of irradiated CAR-NK cells partially suppressed tumor burden as evidenced by reduced serum hsIL-2R levels, although survival benefit did not reach statistical significance. These findings suggest that CAR-NK cell therapy targeting ATL-associated aberrant glycan epitopes represents a potentially valuable therapeutic approach warranting further investigation.
2026-03-28 | How We Evaluate and Treat Leukemic Presentations of Mature T-Cell Lymphomas.
T-cell non-Hodgkin lymphomas, which arise from post-thymic mature T cells, constitute approximately 10-15% of all non-Hodgkin lymphomas. Their leukemic presentations, referred to here as mature T-cell leukemias, are relatively uncommon and present significant diagnostic and therapeutic challenges requiring an informed approach to diagnosis and management. The initial presentation is often persistent T-cell lymphocytosis that must be distinguished from reactive (non-malignant) causes. Unlike B-cell lymphocytosis, where clonality usually indicates malignancy, T-cell clonality can be detected in benign conditions such as autoimmune disorders and viral infections. Thus, establishing clonality is helpful but not sufficient, and a systematic diagnostic approach integrating clinical features, morphology, immunophenotype, and molecular findings is critical. This review outlines our approach to the diagnosis and treatment of four major subtypes of mature T-cell leukemias: T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), T-large granular lymphocytic leukemia (T-LGL), and Sézary syndrome (SS). Each section includes a discussion of clinical features, workup, and treatment options.
other
2026-06-04 | HTLV-1 Tax and HBZ cooperatively promote leukemogenesis through miR-155-mediated PTEN suppression and PI3K-Akt activation.
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), but the full scope of its oncogenic mechanisms remains elusive. While the viral oncoprotein Tax drives early oncogenesis, its expression is frequently silenced in later stages of ATLL, whereas the HTLV-1 basic leucine zipper factor (HBZ) is constitutively expressed throughout infection. This shifting viral expression profile underscores the critical need to define HBZ-specific oncogenic mechanisms. Here, we identify miR-155 as a key oncogenic driver in ATLL and reveal a novel, HBZ-dependent post-transcriptional regulatory axis that sustains its overexpression. We confirm Tax-mediated transcriptional activation of miR-155 but further demonstrate that HBZ enhances miR-155 maturation by elevating Dicer expression and promoting its processing of pre-miR-155. The elevated miR-155 promotes tumorigenesis through targeting PTEN and activating PI3K-Akt pathway. Functional studies demonstrate that miR-155 overexpression drives ATLL progression by enhancing proliferation and inhibiting apoptosis, while its inhibition reverses these malignant phenotypes. Xenograft models confirm that miR-155 blockade significantly reduces tumor growth. Our results uncover a cooperative mechanism by which HTLV-1 Tax and HBZ jointly drive miR-155 overexpression to promote leukemogenesis and identify miR-155 as a potential therapeutic target in ATLL. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive cancer caused by HTLV-1 with limited treatment options. We show that HTLV-1 hijacks the host microRNA miR-155 to drive tumor growth. While the viral protein Tax activates miR-155 transcription, we discovered that HBZ-constitutively expressed even when Tax is silenced-sustains miR-155 expression by upregulating Dicer and enhancing miR-155 processing. Elevated miR-155 then suppresses PTEN and activates the PI3K-Akt pathway, promoting cancer cell proliferation. Importantly, blocking miR-155 significantly reduces tumor growth in mouse models, identifying miR-155 as a promising therapeutic target for ATLL.
2026-06-01 | Human T-Lymphotropic Virus Type 1 (HTLV-1): Molecular Markers, Immunopathogenesis and Future Perspectives for Vaccine Development and Immunotherapy in Adult T-Cell Leukemia/ Lymphoma
Background: Human T-lymphotropic virus type 1 (HTLV-1) is a complex oncogenic delta-retrovirus and the causative agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).Infecting an estimated 5-10 million individuals globally, the virus exerts its oncogenic potential through two pivotal regulatory proteins: Tax and the HTLV-1 basic leucine zipper factor (HBZ), which orchestrate a cascade of molecular events including NF-κB activation, epigenetic reprogramming, immune evasion and clonal T-cell expansion.Despite decades of research, no prophylactic or therapeutic vaccine has received clinical approval.Objectives: This review comprehensively synthesizes current knowledge on HTLV-1 molecular pathogenesis, key molecular biomarkers, HLA-restriction of immune responses and emerging vaccine strategies including peptide-based, DNA-based, mRNA-based, viral vector and dendritic cell-based platforms.It further explores the therapeutic landscape of ATLL including mogamulizumab (anti-CCR4), CAR-T cell therapy and checkpoint inhibitors. Methods:A systematic narrative review of literature from PubMed, Scopus and Web of Science was performed, incorporating 50 peer-reviewed references spanning foundational discoveries to recent clinical trials as of 2024. Conclusion:The molecular complexity of HTLV-1 -particularly the dichotomous roles of Tax and HBZ, HLA-restricted CTL immunodominance and proviral load as a prognostic biomarker -offers multiple actionable targets for next-generation vaccine and immunotherapy design.Integrating multi-epitope mRNA platforms, HBZ-directed CTL induction and combination immunotherapy holds transformative promise for this neglected yet lethal retroviral malignancy.
2026-05-06 | Design and in silico evaluation of an mRNA vaccine against HTLV-1 using AI-driven reverse vaccinology approaches.
Human T-lymphotropic virus type 1 (HTLV-1) is the first discovered human oncogenic retrovirus that can cause adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis, and several other diseases. Due to the poor prognosis of these diseases and the limited therapeutic modalities, the need for an HTLV-1 vaccine is crucial. The current study has used an artificial intelligence-driven reverse vaccinology approach to design an mRNA vaccine against HTLV-1. The two most antigenic proteins of the virus were selected and analyzed using multiple immunoinformatics tools to identify the antigenic immunodominant epitopes for T- and B-cells. Subsequently, the final selected epitopes and the adjuvant were connected using proper linkers. Subsequently, multiple 3D structures were modeled for the vaccine. After refining and evaluating the modeled structures, the best model was selected as the final candidate vaccine structure. The proposed mRNA structure is a potential vaccine with suitable immunological and physicochemical properties against HTLV-1. Docking and simulation analyses showed a proper interaction between the vaccine and the corresponding receptor of the employed adjuvant. However, additional experimental studies are required to further confirm the vaccine's efficacy.
2026-02-05 | Suppressor of cytokine signaling (SOCS) proteins in human retroviral infections.
Retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) have evolved sophisticated mechanisms to establish persistent infection by manipulating host immune signaling networks. A central target of this viral interference is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which governs cytokine-, interferon-, and growth factor–mediated immune responses. Tight control of this pathway is mediated by the suppressor of cytokine signaling (SOCS) protein family, comprising eight members (SOCS1–SOCS7 and cytokine-inducible SH2-containing protein, CIS) that function as inducible negative feedback regulators of JAK activity and cytokine receptor signaling. Accumulating evidence indicates that HIV-1 and HTLV-1 exploit SOCS proteins most prominently SOCS1 and SOCS3 to dampen antiviral interferon signaling, inhibit STAT activation, impair antigen presentation, and promote viral persistence. In HTLV-1 infection, dysregulation of SOCS expression further contributes to the survival, proliferation, and immune evasion of infected T cells, implicating SOCS pathways in the pathogenesis of adult T-cell leukemia/lymphoma. Despite these insights, the majority of studies have focused narrowly on SOCS1 and SOCS3, leaving the roles of other SOCS family members largely unexplored. This mini-review summarizes current knowledge on SOCS-mediated modulation of JAK/STAT signaling in HIV-1 and HTLV-1 infections, identifies critical gaps in our understanding of SOCS family diversity in retroviral immune evasion, and discusses the therapeutic potential of targeting SOCS pathways to restore antiviral immunity and limit retrovirus-associated disease.
2025-12-09 | Intra-pol proviral open region of HTLV-1 controls the transcription from both long terminal repeats.
Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+ T lymphocytes and causes both malignant and inflammatory diseases: the aggressive malignancy known as Adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory syndromes. HTLV-1 infection is established by integration of proviral DNA (~9000 bp) into the host genome. In HTLV-1, two viral genes, tax and HBZ, play critical roles in viral transcription and promotion of T-cell proliferation, respectively. The present study was undertaken to test the hypothesis that the higher-order structure of proviral chromatin regulates its transcription on both the plus strand and the minus strand. ATAC-seq analysis identified an open chromatin region in the pol gene of proviral DNA, which we name IPOR, in many ATL cases. Using reporter assays, it was found that the sequence of IPOR suppresses the transcription of the plus strand and activates that of the minus strand. Binding motifs of Eomes and TEAD proteins were predicted in this region, and we confirmed recruitment of the transcription factors to their respective motifs by ChIP-qPCR. A mutant of IPOR which cannot bind the transcription factors weakened the transcriptional activating effects compared with the wild type, suggesting that the IPOR and those transcription factors suppress the 5' long terminal repeat (LTR) but activate the 3'LTR. In addition, a mutant HTLV-1 molecular clone, which possesses the IPOR mutant, produced a higher titer of virus than the wild type. RNA-seq analysis of HTLV-1-infected cell lines, in which Tax expression can be traced after induction, revealed that EOMES expression decreases during the tax transcriptional burst and resumes following termination of the burst. These findings suggested that the expression dynamics of Eomes affect the transient expression of Tax. The IPOR sequence appears to regulate the transcription from both LTRs, suppressing the 5'LTR but activating the 3'LTR. Recruitment of Eomes to the IPOR is likely to influence the expression of Tax and HBZ. Since both viral genes are involved in diverse mechanisms for viral replication, cellular proliferation, and immune regulation, the IPOR may play a role in fine-tuning the modes of viral persistence in vivo.
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Drug Discovery Landscape
6 orphan drug designations for Adult T-cell leukemia/lymphoma.
6 orphan drug designations for Adult T-cell leukemia/lymphoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
mRNA cancer vaccine containing the nucleoside-modified mRNAs encoding EBNA1, LMP1, and LMP2 proteins of Epstein-Barr virus (EBV) | vaccines | FDA | — | WestGene Biopharma Co., Ltd. |
small molecule cytidine triphosphate synthase 1 (CTPS1) inhibitor | small molecules | FDA | Step Pharma | |
a fully human immunoglobulin G1 (IgG1) monoclonal anti-tumor necrosis factor receptor 2 (TNFR2) antibody | antibodies | FDA | BioInvent International AB | |
brentuximab vedotin | antibodies | FDA | Seattle Genetics, Inc. | |
A lentiviral vector pseudotyped by the Indiana serotype of the vesicular stomatitis virus G protein encoding an antigen derived from the Tax, HBZ, p12I and p30II HTLV-1 proteins | gene therapies | EMA | — | THERAVECTYS |
mogamulizumab | antibodies | FDA | Kyowa Kirin Pharmaceutical Development, Inc. |
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