RARE DISEASE
Precursor T-cell acute lymphoblastic leukemia
Precursor T-cell acute lymphoblastic leukemia
Precursor T-cell acute lymphoblastic leukemia
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Drug discovery
2,966
papers
On emerging therapies
Overview
Precursor T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T-cell precursors, characterized by bone marrow/blood involvement, mediastinal masses, and extramedullary disease. Diagnosis requires >25% bone marrow blasts and T-lineage markers (cCD3+, CD7+). Prognosis varies by age and genetic risk, with relapse rates of 15-30% despite intensive therapy [1][4][6][14].
Burden
Survival: 85% 5-year EFS in pediatric vs. 40-60% in adult patients; ETP-ALL has <40% 5-year OS in adults [4][6][17].
Relapse: 28-30% relapse risk despite nelarabine integration; median survival post-relapse is <1 year [4][5].
Toxicity: 70-80% experience severe infections or cytopenias during induction/consolidation [8][17].
Therapies
Chemotherapy: Dexamethasone-based induction with nelarabine (for CNS prophylaxis) augmented by asparaginase and anthracyclines [5][17].
Targeted agents: Bortezomib (NOTCH1 inhibition), ruxolitinib (JAK/STAT in ETP-ALL), venetoclax (BCL-2 inhibition), and CD38-directed therapies [3][4][13].
Transplant: Allo-HSCT recommended for high-risk/relapsed disease or persistent MRD [4][17].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
2,966 drug discovery papers about Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,966 drug discovery papers about Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-29 | Expression of miR-214 in Pediatric Acute Leukemia: Correlations with Leukemia Subtypes, Familial Predisposition, and Hepatitis B Virus Infection.
miR-214 dysregulation has been implicated in various cancers, yet its role in pediatric acute lymphoblastic leukemia (ALL) is not fully understood. This study evaluated miR-214 expression in newly diagnosed pediatric ALL patients and explored associations with leukemia subtypes, family history, and hepatitis B virus (HBV) infection. Bone marrow aspirates were collected from 44 pediatric ALL patients (26 B-ALL, 18 T-ALL) and five non-leukemic controls. qRT-PCR quantified miR-214 expression. Clinical data included HBV status and family history of hematologic malignancy. Relative expression levels were analyzed using 2-ΔΔCt and log₁₀ transformed for statistical analyses, including correlation and logistic regression models with interaction terms. The present study aimed to quantitatively evaluate the expression pattern of miR-214 in newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients compared with non-leukemic controls. In addition, the study sought to investigate whether miR-214 expression differs according to immunophenotypic subtype (B-ALL versus T-ALL) and to explore its potential associations with clinical and host-related factors, specifically family history of hematologic malignancy and hepatitis B virus (HBV) infection status. Furthermore, this study aimed to assess whether these variables exert interaction effects that may reflect context-dependent regulation of miR-214 in pediatric leukemogenesis. miR-214 expression was generally downregulated in ALL compared to controls, though differences were not statistically significant. B-ALL patients showed lower median expression than T-ALL, with the lowest levels observed in those with a positive family history. T-ALL patients exhibited broader expression variability, including marked upregulation in some cases. Exploratory regression models suggested differential effects of miR-214 based on HBV status and family history, but interaction terms did not reach statistical significance (p > 0.05). miR-214 expression in pediatric ALL appears to vary according to leukemia subtype and selected clinical factors, including family history and HBV infection. However, no statistically significant interaction effects were observed. These findings should be considered preliminary and warrant validation in larger, adequately powered cohorts to clarify the potential clinical relevance of miR-214 in leukemogenesis.
2026-09-29 | Lineage Plasticity-Mediated Resistance to CD7-Directed CAR-T Therapy in Relapsed/Refractory T-ALL/LBL.
CD7-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL). However, relapse remains a major obstacle. We generated a recyclable CD7 CAR-T cells (CD7 CARRecyclable) and conducted a phase I clinical trial to evaluate its safety and response in patients with R/R T-ALL/LBL (NCT05290155). Fourteen patients received CAR-T cells and were evaluable for safety and response. Immunophenotypic and molecular profiling were performed longitudinally to characterize relapse patterns. Robust CAR-T expansion was observed in 13 of 14 patients (92.9%). Peak CAR-T concentration (Cmax) reached 62,389.69 copies/μg DNA (range: 3,175.94-326,482.67) at median 12 days post-infusion (range: 10-21). All patients experienced hematologic toxicities, and cytokine release syndrome occurred in 71.4% of patients, predominantly grade 1-2. While ICANS developed in 2 patients (14.3%, grade 2 and 3) at day 8 and 28, respectively. Three out of four patients achieved measurable residual disease (MRD) -negative complete remission in bone marrow, while the objective response rate for extramedullary disease was 78.6%. With a median follow-up of 8.5 months, the estimated 6-month overall survival (OS) and progression-free survival (PFS) were 62.3% and 44.6%, respectively. Notably, lineage switch relapse occurred in two patients with ETP-immunophenotype following CAR-T therapy. These findings suggest that lineage plasticity might represent an under-recognized mechanism of resistance to CD7-directed CAR-T therapy in T-ALL/LBL, particularly in ETP-ALL/LBL, warranting further exploring.
2026-09-25 | Targeting the tumor, harboring the host: IL-7 receptor-targeted CARs to treat T-ALL
Chimeric antigen receptor (CAR) T cell therapy has fundamentally transformed clinical outcomes in B cell malignancies; however, the success story of CAR T cells has not yet extended to T cell acute lymphoblastic leukemia (T-ALL). A primary issue lies in the fundamental biology of the disease; most target antigens are shared between malignant T-ALL blasts and healthy T lymphocytes, including the CAR T cell product itself.
2026-08-24 | Efficacy, Safety, and Kinetics of Naturally Selected Anti‐ CD7 CAR ‐T Cell Therapy in T‐ ALL / LBL With CNS Leukemia
To the Editor, Central nervous system leukemia (CNSL) remains one of the most challenging manifestations of relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL).Despite intensive therapy, outcomes after CNS relapse remain poor and treatment options are limited [1-3].CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in R/R T-ALL/LBL, with complete remission (CR) rates approaching 90% [4][5][6][7].However, whether CD7 CAR-T cells can effectively traffic to and eradicate CNSL without excessive neurotoxicity remains poorly defined.
2026-07-20 | Research trends and hotspots of CAR-T cell therapy for acute lymphoblastic leukemia: A bibliometric analysis.
This study aims to analyze the global research patterns and emerging trends in CAR-T cell therapy for ALL through a bibliometric analysis. Publications were retrieved from the Web of Science Core Collection database. The bibliometric analysis utilized VOSviewer, CiteSpace, and the R package "bibliometrix" to visualize collaborations, keyword co-occurrences, and emerging research trends. A total of 844 articles from 253 journals by 6,459 authors across 44 countries were analyzed, showing an annual growth rate of 40.08%. The USA (372 articles, 38,065 citations) and China (275 articles, 5,636 citations) dominated research output. The University of Pennsylvania (353 articles), Memorial Sloan Kettering Cancer Center (170), and Children's Hospital of Philadelphia (131) were the most productive institutions, while Blood (41 articles) published the most articles. Stephan A. Grupp (38 articles, H-index = 30), Carl H. June (26 articles, H-index = 24), and Shannon L. Maude (25 articles, H-index = 20) were the most influential authors. Keyword analysis revealed five research clusters, including basic mechanisms, CAR design, population treatment integration, clinical outcomes, and toxicity management. Burst keyword analysis showed the evolution from basic science (2010-2013) to clinical translation (2014-2016), toxicity management (2017-2019), and recently to long-term outcomes and risk assessment (2020-2024), with "term follow-up" and "risk" as the only keywords with active bursts in 2024. This bibliometric analysis reveals that research on CAR-T therapy for ALL has progressed from foundational concepts to clinical implementation and now focuses on optimizing long-term outcomes and patient selection. Future research should prioritize biomarker development, next-generation CAR designs, and combination strategies to overcome persistence, toxicity, and resistance limitations in ALL treatment.
antibodies
2026-09-26 | Comparative In Vitro Apoptotic Activity of Two Chimeric Anti-CD99 Antibodies Recognizing Distinct CD99 Regions in T-ALL Models.
Background/Objectives: Therapeutic antibodies have become an important modality for cancer treatment; however, effective targeted antibody therapies for T-cell acute lymphoblastic leukemia (T-ALL) remain limited. CD99 is a promising therapeutic target due to its high expression in leukemic T cells and its capacity to transmit apoptotic signals. However, the efficacy of antibody-mediated apoptosis may depend on the CD99 region recognized by the antibody. This study compared the in vitro apoptotic activity of two chimeric anti-CD99 antibodies, ChAbMT99/1 and ChAbMT99/3, which recognize distinct regions of CD99 in T-ALL models. Methods: ChAbMT99/1 and ChAbMT99/3 were generated as human IgG1 antibodies. Antibody reactivity and binding site specificity were characterized using peptide-based ELISA. Binding to native CD99, apoptosis induction in two-dimensional (2D) Jurkat E6.1 and MOLT-4 suspension cultures and three-dimensional (3D) Jurkat E6.1-derived spheroid models, and cytotoxic effects on peripheral blood mononuclear cells (PBMCs) were assessed by flow cytometry. In vitro hematologic effects were assessed using hemagglutination and platelet aggregation assays. Results: ChAbMT99/1 and ChAbMT99/3 specifically recognized peptides corresponding to distinct CD99 regions, with peptide-binding EC50 values of 0.813 and 0.819 μg/mL, respectively. Both antibodies exhibited binding reactivity to native CD99 on the tested cells. Functionally, both antibodies induced Annexin V/7-AAD-defined cell death in both 2D and 3D T-ALL models compared with controls in a crosslinking-dependent manner. In contrast, both antibodies induced low levels of cell death (<10%) in bulk PBMCs, with no visible hemagglutination or platelet aggregation observed in samples from five selected donors under the stated assay conditions. Conclusions: Both chimeric anti-CD99 antibodies demonstrated in vitro apoptotic activity against T-ALL models despite recognizing distinct regions of CD99. These findings provide a rationale for further investigation of their other mechanisms of action to support the future development of CD99-targeted antibody therapy for T-ALL.
2026-09-16 | Daratumumab in Combination With High-Dose Cytarabine and Amsacrine as an Effective Salvage Therapy and Bridge to Allogeneic Hematopoietic Stem Cell Transplantation for Refractory T-Cell Acute Lymphoblastic Leukemia: A Case Report.
Patients with refractory or relapsed T-cell acute lymphoblastic leukemia (R/R T-ALL) have dismal outcomes. While immunotherapies are growing opportunities for B-cell ALL, targeted therapies for T-ALL remain limited. The CD38 antigen, steadily expressed on T-ALL blasts, represents a relevant therapeutic target. Daratumumab, an anti-CD38 monoclonal antibody routinely used in other hematologic malignancies, could be a promising treatment option for T-ALL. We report here the achievement of a third complete response with the combination of daratumumab, high-dose cytarabine (18 g/m2), and amsacrine in an 11-year-old patient with highly aggressive relapsed T-ALL, enabling subsequent allogeneic hematopoietic stem cell transplantation.
2026-09-15 | Targeting CD38 with bispecific antibody XmAb 18968 in patients with relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia.
CD38 is a transmembrane glycoprotein highly expressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to reduce non-selective activation of effector cells. In this phase 1 multicenter clinical trial, we evaluated the outcomes of XmAb18968 in adults with relapsed/refractory (RR) AML and T-ALL. Twenty-two patients with AML (n = 13) and T-ALL (n = 9) with a median age of 63 years (range 31-77) were enrolled. Prior lines of therapy (median 3, range 1-8) included venetoclax (77.3%), allogeneic HCT (22.7%), CD7 CAR-T cell therapy and daratumumab (11.1%). Grade ≥3 adverse events included anemia (14%), neutropenia (18%), and thrombocytopenia (14%). No grade ≥3 cytokine release syndrome or neurotoxicity was seen. Overall, 17 patients (AML = 11, ALL = 6) completed at least one cycle of therapy. Among 11 patients with RR-AML, one achieved partial remission (PR) and two achieved MRD negative complete remission (CR). In 6 patients with RR-T-ALL, 4 achieved meaningful improvement in disease burden with 1 clearance of MRD. Median OS was 8.5 months in AML and 8.7 months in T-ALL. XmAb18968 is safe and tolerable with encouraging preliminary efficacy, supporting further investigation of CD38 targeting therapies in this setting (NCT05038644).
2026-08-28 | Targeting CD38 in relapsed /refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy.
Relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) has poor outcomes and limited salvage options. Objectives: To evaluate the efficacy and safety of daratumumab-based therapy in R/R T-ALL/T-LBL. Systematic review of observational reports. Sixteen reports including 34 patients treated with daratumumab-based regimens were reviewed. Baseline characteristics, treatment patterns, response, MRD status, survival, allogeneic HSCT, and safety were descriptively synthesized. Complete remission was reported in 30/34 patients (88.2%), partial remission in 2/34 (5.9%), and no response in 2/34 (5.9%). Among complete responders with reported MRD status, 24/29 (82.8%) achieved MRD negativity. Median PFS was 10 months (range, 0.4-45), and median OS was 10 months (range, 1.5-45), although many values reflected last follow-up. Eighteen patients (52.9%) proceeded to allogeneic HSCT; 13/18 (72.2%) were alive at last follow-up. Infusion reactions occurred in 10 patients, mostly grade 1-2. Daratumumab-based therapy may induce remission and facilitate HSCT bridging in selected patients, but findings remain hypothesis-generating because evidence is mainly from case reports and small series.
2026-07-28 | T-ALL Elicits Robust T Cell Responses Despite Low Tumor Mutational Burden in multiple tissues with distinct TMEs 2267295
Abstract Introduction T-cell acute lymphoblastic leukemia (T-ALL) is a devastating pediatric malignancy arising from immature T cells. Despite improved survival rates, treatment still relies on intensive, toxic chemotherapy that fails to cure all patients. More effective and targeted therapies are urgently needed. Most immunotherapy efforts in T-ALL have focused on engineered cells (e.g., CAR T cells), while strategies leveraging patients’ pre-existing anti-tumor T cells remain largely unexplored. This is partly due to the assumption that T-ALL’s low tumor mutational burden (TMB) limits immunogenicity. However, our data challenge this paradigm using both murine models and patient samples. Methods We used murine transplantation models in which spontaneous T-ALL from CD45.2+ LN3 or LMO2 mice were transferred into immune-competent CD45.1+ congenic hosts, allowing distinction between malignant and host T cells. OTI/II and NUR77-GFP mice were used to assess TCR-dependent activation. Results T-ALL-bearing mice showed high frequencies of TOX+PD-1+ T cells, consistent with chronic, antigen-specific activation. Ex vivo stimulation revealed that PD-1+ T cells retained function, with increased IFN-γ production. To confirm TCR specificity, we transplanted T-ALL into OT-I/II mice (OVA-specific), where exhausted phenotypes were not induced–supporting a TCR-dependent mechanism. NUR77-GFP mice further confirmed high TCR signal strength in T cells from T-ALL-bearing hosts. Finally, treatment with aPD-1 or aCD40 improved survival, with enhanced benefit in combination. Conclusion These findings provide proof-of-concept that robust, functional, leukemia-specific T cell responses are mounted against T-ALL despite low TMB. This challenges existing dogma and supports the development of immunotherapy strategies that activate endogenous T cells. Ongoing studies aim to define how divergent tumor microenvironments regulate these responses and identify targets for rational combination immunotherapy. Funding Source na Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
small molecules
2026-09-29 | The Novel Organic Arsenical PZ2 Exhibits Potent Anti-T-ALL Activity via ROS-Dependent Apoptosis and GABARAPL1-Induced Autophagic Cell Death
Objective: T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological malignancy with poor overall prognosis. This study systematically evaluates the anti-leukemic therapeutic potential and underlying redox-driven mechanisms of PZ2, a novel organic arsenic compound, in T-ALL. Methods: The cytotoxicity of PZ2 against T-ALL cell lines and normal cells was assessed to determine its therapeutic window. RNA-seq was utilized to map transcriptomic alterations. Intracellular redox homeostasis, mitochondrial membrane potential (MMP), cell cycle, and apoptosis were evaluated using flow cytometry and fluorescence microscopy. Ultrastructural changes and key protein expressions were analyzed via TEM, RT-qPCR, and immunoblotting. In vivo efficacy was validated using a T-ALL cell-line-derived xenograft (CDX) mouse model. Results: PZ2 exhibited superior cytotoxicity and an improved safety profile compared to inorganic arsenic trioxide (ATO). Transcriptomic data indicated strong enrichment in apoptosis and autophagy–lysosome pathways. PZ2 induced profound mitochondrial oxidative stress, leading to ROS accumulation, MMP loss, and subsequent activation of caspase-dependent apoptosis—effects that were completely rescued by ROS scavengers. Furthermore, PZ2 triggered G2/M phase arrest and activated autophagic flux (upregulated GABARAPL1 and LC3-II, degraded p62). Notably, pharmacological inhibition of autophagy rescued PZ2-induced apoptosis, revealing a pro-death autophagic mechanism. In vivo, PZ2 significantly suppressed tumor growth and prolonged survival without overt systemic toxicity. Conclusions: PZ2 exhibits potent anti-T-ALL activity that may involve a dual mechanism: ROS-dependent mitochondrial apoptosis and pro-death autophagy potentially associated with GABARAPL1. This novel organic arsenical may represent a promising and potentially safer alternative for leukemia therapy, and these findings suggest a potential interplay between oxidative stress and autophagic cell death.
2026-09-25 | Case Report: Clinical response to TKI therapy in T-cell acute lymphoblastic leukemia with rare ABL1 rearrangement.
T-cell acute lymphoblastic leukemia (T-ALL) with ABL1 rearrangement is an extremely rare disease, and its clinical significance has not been precisely defined. We report the clinical characteristics of a pediatric patient with T-cell acute lymphoblastic leukemia harboring ABL1 rearrangement and the treatment response to tyrosine kinase inhibitor (TKI) therapy, providing a reference for clinical management with this subtype. A 3-year-old boy with T-ALL and ZBTB16::ABL1 fusion (RNA-seq) showed poor response to induction chemotherapy, failing remission at D33. Dasatinib (75 mg/m2/day) was added concurrently with CAM chemotherapy. At D90, morphological CR and flow-MRD negativity were achieved, though qPCR remained positive at 0.08%. Isolated CNS relapse occurred during Block III consolidation. Subsequent management included autologous CD7 CAR T-cell therapy and allogeneic HSCT; post-transplant evaluation confirmed sustained leukemia remission. However, the patient developed HHV-6 encephalitis and adenovirus hepatitis with hepatic failure; life-sustaining support was withdrawn at the family's request. The patient was discharged and lost to follow-up. This paper presents the second reported case to date of TKI treatment for T-cell acute lymphoblastic leukemia harboring the ZBTB16::ABL1 fusion. Following a review of the relevant literature on ABL1-rearranged T-ALL, we conclude that the accumulation of additional cases is essential to better characterize this rare molecular subtype and to guide evidence-based treatment decisions.
2026-09-17 | Metabolic reprogramming in T-cell acute lymphoblastic leukemia: Mechanisms of therapy resistance and clinical applications.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which therapy resistance remains a major cause of treatment failure and relapse. Increasing evidence indicates that metabolic reprogramming and metabolic plasticity can contribute to T-ALL persistence under therapeutic pressure, rather than reflecting a single uniform metabolic phenotype. In this review, we examine the reprogramming of glucose, amino acid, lipid, and nucleotide metabolism, as well as metabolic adaptations within the tumor microenvironment, and their associations with therapy resistance in T-ALL. We further discuss the regulatory roles of oncogenic signaling pathways and metabolism-epigenetics crosstalk in metabolic adaptation. Emerging metabolism-targeted strategies are also reviewed, with particular attention to their potential therapeutic vulnerabilities and the evidence supporting their use in different experimental and clinical contexts. Major barriers to clinical translation include metabolic heterogeneity, compensatory metabolic rewiring, and toxicity arising from metabolic dependencies shared with normal tissues. Future metabolic-directed therapies require precise metabolic subtyping guided by multi-omics approaches, the development of novel targeted drugs, and the implementation of rational combination therapies.
2026-09-10 | ENCERT: A Multisite Phase 1 Trial Using Everolimus in Combination With Nelarabine, Cyclophosphamide, and Etoposide in Relapsed T-Cell Lymphoblastic Leukemia/Lymphoma.
Relapsed and refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) remains a therapeutic challenge. Allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR) offers the only chance of cure, but effective modalities to achieve CR are limited. Activation of mTOR and PI3K pathways has been well described in T-ALL and monotherapy with mTOR inhibitors has shown efficacy signals used in relapsed disease. This multisite Phase 1 study evaluated the safety, tolerability, and anti-leukemic activity of everolimus with NEC chemotherapy (nelarabine, etoposide, and cyclophosphamide) among children and young adults with relapsed/refractory T-ALL/T-LL. Eight patients were enrolled to two dose levels (DLs) on this study and no dose-limiting toxicities were reported. Most adverse events related to therapy were expected and hematological. DL2 (n = 5) of everolimus at 5 mg/m2/day was the highest dose tested. The overall response rate (complete response + complete response with incomplete platelet recovery + partial response) was 75% (6/8) with 100% (5/5) responses in the T-ALL cohort and 33% (1/3) responses in T-LL cohort. All six patients who obtained a PR or greater proceeded to receive HSCT as consolidation therapy. Two of the six patients transplanted are alive today with two deaths related to progressive disease and two related to veno-occlusive disease post transplantation. This study demonstrates safety with a combination of everolimus and NEC chemotherapy. Given the observed tolerability and efficacy of everolimus with NEC in this small cohort of patients, this combination should be further evaluated in larger phase 2/3 clinical trials. ClinicalTrials.gov identifier: NCT03328104.
2026-08-28 | Venetoclax with azacitidine and dexamethasone: Non-cytotoxic induction therapy for T-cell leukemia and mixed-phenotype leukemia.
T-lineage acute leukemias are aggressive malignancies for which treatment options are limited. This study evaluated the efficacy and safety of a non-cytotoxic regimen combining venetoclax, azacitidine, and dexamethasone (VAD) as first-line induction therapy for T-cell acute lymphoblastic leukemia (T-ALL) and T/myeloid mixed-phenotype acute leukemia (T-Myeloid MPAL). We retrospectively analyzed the clinical parameters and survival data of 11 patients with newly-diagnosed T-ALL or T-Myeloid MPAL who received the VAD regimen. The complete remission (CR) rate and adverse events were assessed. Kaplan-Meier curves were constructed to evaluate survival outcomes. Among 11 patients (7 with early T-cell precursor [ETP] ALL, 2 with T-Myeloid MPAL, and 2 with non-ETP T-ALL), the overall CR rate after one cycle of VAD therapy was 90.9%, with 45.5% achieving measurable residual disease (MRD) negativity by flow cytometry. The historically poor-prognosis ETP-ALL subgroup showed an 85.7% CR rate (6/7), while both T-Myeloid MPAL cases attained MRD negativity. No tumor lysis syndrome or treatment-related mortality occurred. Over a median follow-up of 358 days, all 5 patients who received transplantations remained relapse-free. The VAD regimen demonstrated a high response rate and favorable safety, enabling effective transplantation bridging with avoidance of conventional cytotoxic therapy.
oligonucleotides
2025-10-22 | Characterization of a PRKCE::ETV6 fusion as a potential oncogenic driver in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by mutation accumulation during hematopoiesis. The characterization of chromosomal abnormalities may provide significant insights into genetic mechanisms of malignant transformation in hematopoietic cells. However, T-ALL is genetically very heterogenous and driving mutations as well as clonal markers for the assessment of minimal residual disease are not always identifiable. Hence, there is a clinical need to further refine the genetic landscape of T-ALL including previously unrecognized fusion partners of commonly translocated genes in T-ALL of childhood. In this study, we screened n = 229 T-ALL cases by our targeted genomic capture high-throughput sequencing (gc-HTS) approach. In total, we identified n = 60 gene–gene fusions, present in n = 57 (25%) of the patients. Nine rare or even unrecognized translocations were identified and validated. Furthermore, owing to its interesting chromosomal structure, we studied the oncogenic potential of the complex rearrangement of chromosome 2 and 12, found in a near-early T-cell progenitor (ETP) ALL that leads to the fusion events PRKCE::ETV6 and ETV6::INO80D. Exogenous expression of PRKCE::ETV6 in Ba/F3 pro-B and D1 T-cells caused interleukin-independent proliferation and enhanced survival upon interleukin withdrawal, respectively. Our study underlines the heterogenous mutational landscape in T-ALL. The previously unrecognized PRKCE::ETV6 resulting from a complex rearrangement involving chromosome 2 and 12 demonstrated transforming potential in cytokine-dependent cellular models support the notion of a driver mutation in near ETP-ALL. Our data reconfirm the relevance of ETV6-fusion proteins in the pathogenesis of undifferentiated T-ALL. Importantly, genomic breakpoints at the ETV6 locus represent potentially robust MRD markers for (near) ETP-ALL that lack IG/TR rearrangements. The online version contains supplementary material available at 10.1186/s40348-025-00208-x.
2024-11-25 | Aptamer sgc8-Modified PAMAM Nanoparticles for Targeted siRNA Delivery to Inhibit BCL11B in T-Cell Acute Lymphoblastic Leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease with limited targeted therapy options. Overexpression of B-cell lymphoma/leukemia 11B is frequently observed in T-ALL and contributes to leukemogenesis. Knockdown of BCL11B inhibits T-ALL cell proliferation and induces apoptosis, making it a potential therapeutic target. However, the clinical application of siRNA therapies is hindered by challenges such as poor delivery efficiency and limited clinical outcomes. We developed a targeted delivery system for BCL11B siRNA (siBCL11B) using generation 5 polyamidoamine (G5-PAMAM) dendrimers conjugated with the sgc8 aptamer, which specifically binds to the T-ALL cell membrane protein PTK7. This nanoparticle, designated G5-sgc8-siBCL11B, was designed to selectively deliver siRNA to T-ALL cells. In vitro and in vivo experiments were conducted to evaluate its therapeutic efficacy and safety. We demonstrate that sgc8-conjugated siBCL11B nanoparticles selectively and efficiently target BCL11B-overexpressing T-ALL cells, significantly inhibiting cell viability and promoting apoptosis while exhibiting minimal impact on the viability of normal T cells. In T-ALL mouse model studies, G5-sgc8-siBCL11B and G5-siBCL11B significantly inhibited the progression of T-ALL in vivo, extending the survival of mice compared to the control (CTR), G5, and G5-sgc8 groups. Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993). The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.
2024-04-12 | Limited dsRNA editing impedes leukemia stem cells.
Understanding the mechanisms underlying the generation and maintenance of leukemia stem cells (LSCs) is crucial for the development of effective therapies against T cell acute lymphoblastic leukemia (T-ALL). In a recent study, Rivera et al. discovered that elevated adenosine deaminase acting on RNA (ADAR)-1-mediated RNA editing is a distinguishing feature of T-ALL relapse, and that ADAR1 suppresses apoptosis triggered by the double-stranded (ds)RNA-sensing pathway.
2024-03-04 | Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.
Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T-ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, we uncover that the cell-intrinsic level of MDA5 dictates the dependency on the ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.
2024-01-08 | Involvement of TAL1-microRNA Axis in the Progression of T-cell Acute Lymphoblastic Leukemia
The T-cell acute lymphoblastic leukemia 1 (TAL-1) transcription factor is crucial for T-cell differentiation, but the ectopic expression in 30% of cases can disrupt normal differentiation, and promote cancer progression. This can be due to microRNA (miRNA) dysregulation or other oncogenes. The present study covers articles related to T-cell acute lymphoblastic leukemia (T-ALL), TAL-1 and miRNA, which were published in the English language from 1994 to 2023. After analyzing the research, it is evident that the TAL-1 overexpression is associated with alterations in several miRNAs, which encompass both those that suppress tumors, and those that stimulate cell growth. The interplay between TAL-1 and miRNAs exhibits diverse dynamics. For example, specific miRNAs, such as miR-223, interact with the TAL-1 gene promoter, resulting in its upregulation. In contrast, the miR-17-92 cluster indirectly influences the stability of the TAL-1 transcription complex. Typically, the interaction between TAL-1 and its associated miRNAs follows a unidirectional pattern, in which miRNAs that target TAL-1 are downregulated, leading to elevated TAL-1 levels. Nevertheless, TAL-1 exhibits a bidirectional relationship with miR-223, in which each positively affects the expression of the other. In addition, there is a cooperative interaction between miR-146-5b and TAL-1. Unlike miR-223, TAL-1 reduces the expression of miR-146-5b, thereby inhibiting tumor growth. Individuals with T-ALL, who experience disruptions in the TAL-1 and miRNA network, often face a poor prognosis, and their tumors tend to be larger. In conclusion, delving deeper into the network of miRNAs associated with TAL-1 in T-ALL offers a novel perspective on cancer prognosis and the development of improved diagnostic and treatment strategies.
other
2026-05-11 | CRISPR Genome Editing and the Future of Leukaemia Immunotherapy.
Leukaemia presents ongoing therapeutic challenges due to relapse and toxicity associated with standard treatments. By enabling more targeted and safer therapies, CRISPR genome editing is emerging as a powerful tool to address these issues. We review current literature on CRISPR technologies in leukaemia immunotherapy, focussing on studies involving four key antigens commonly targeted in leukaemia: CD33, CD7, CD45 and CD19. We trace the evolution of CRISPR technologies from conventional CRISPR-Cas9 to base editing, highlighting how CRISPR platforms are being repurposed to enhance efficacy and clinical safety. Key studies targeting CD33 demonstrate how editing strategies can enable safer acute myeloid leukaemia (AML) therapies by reducing off-tumour toxicity; those addressing CD7 show how base editing prevents T-cell fratricide in T-cell acute lymphoblastic leukaemia (T-ALL) immunotherapy; studies focusing on CD45 illustrate how targeted editing facilitates universal CAR T-cell therapy; and clinical trials on CD19 support the feasibility of "off-the-shelf" treatments against paediatric B-cell acute lymphoblastic leukaemia (B-ALL). While base editing excels in precision and functional preservation, CRISPR-Cas9 remains preferred when complete gene knockout is desired. As off-tumour toxicity and fratricide are addressed, the future clinical impact of these technologies is poised to expand.
2026-04-03 | PERSONALIZED MULTI-EPITOPE PEPTIDE VACCINE DESIGN TARGETING NOTCH1 MUTATIONS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL): A COMPREHENSIVE IMMUNOINFORMATICS ANALYSIS
Large-scale somatic mutation data from COSMIC v97, GenomePaint (St. Jude Cloud), and TARGET/TCGA (N = 1,392 T-ALL samples) were integrated to identify high-frequency hotspot mutations at exons 26–27. Five MHC class I neoepitopes were predicted and stringently filtered using NetMHCpan-4.1, HLAthena, and NetMHCstabpan against a Vietnamese-prevalent HLA allele panel. A multicomponent vaccine construct was assembled incorporating the molecular adjuvant CTB, two universal T-helper epitopes (P2/P30), three MHC class II helper epitopes from NOTCH1 and RHEB, one linear B-cell epitope from NOTCH1, and a clinically validated modified WT1 epitope (CYTWNQMNL). The construct underwent comprehensive evaluation of physicochemical and immunological properties, 3D structure prediction (AlphaFold2/RoseTTAFold2), molecular docking (AutoDock Vina, PatchDock/FireDock), immune simulation (C-ImmSim), and codon optimization (JCat).
2026-04-02 | CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-Cell Acute Lymphoblastic Leukemia (T-ALL) Therapy.
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with limited targeted therapies. CD28, a costimulatory receptor aberrantly overexpressed on T-ALL cells, presents a promising underexplored therapeutic target. In this study, we developed an enzyme-responsive self-assembling peptide, SAp-CD28, designed to target CD28 and undergo receptor-mediated self-assembly in the tumor microenvironment. Upon dephosphorylation by overexpressed phosphatases, SAp-CD28 transitions from an α-helix to a β-sheet/β-turn rich structure, facilitating the formation of nanooligomers that engage CD28 and activate cytotoxic pathways. Transcriptomic and biochemical analyses reveal that SAp-CD28 induces a profound dysregulation of CD28 downstream signaling, characterized by the suppression of the PLCγ and Akt pathways. These signaling perturbations lead to oxidative stress and disruption of intracellular calcium homeostasis, resulting in calcium overload, calpain activation, and cytoskeletal collapse. Besides, confocal imaging suggested that the peptide self-assembly can enter the nucleus and disrupt it. In Jurkat xenograft models, SAp-CD28 demonstrated potent antitumor activity, and its combination with cytarabine resulted in near-complete tumor suppression, highlighting its potential for T-ALL treatment. This work introduces a CD28-targeted, enzyme-activated nanotherapeutic strategy that synergizes biochemical and mechanical mechanisms to selectively eliminate T-ALL cells. This multi-mechanistic tumor-killing strategy can also be extended to inspire therapeutic approaches for other diseases.
2026-01-15 | QKI dysregulation induces extensive splicing changes in T-cell acute lymphoblastic leukemia.
Understanding the molecular mechanisms underlying T-cell acute lymphoblastic leukemia (T-ALL) is essential for developing more effective therapeutic strategies. Despite therapeutic advances, the role of RNA-binding proteins in the pathogenesis of T-ALL remains poorly understood. Here, we investigate the RNA-binding Quaking protein (QKI), identifying it as a key regulator of splicing with tumor-suppressive properties in T-ALL. Through the analysis of two independent pediatric T-ALL cohorts, we demonstrate that QKI expression is frequently reduced in T-ALL, particularly within the HOXA subtype, and this reduction correlates with poor overall and event-free survival. Using T-ALL cell lines, we show that QKI depletion induces widespread splicing alterations, with numerous events corroborated in patient samples. Transcriptome profiling indicates that QKI downregulation leads to broad changes in gene expression, notably affecting pathways related to cell cycle progression, cholesterol homeostasis, and epithelial-mesenchymal transition. Functional assays demonstrate that QKI overexpression in T-ALL cells significantly reduces cell proliferation, induces G0/G1 cell cycle arrest, and limits leukemia progression and dissemination, ultimately improving survival in xenograft models. Together, these findings provide compelling evidence that QKI functions as a regulator of RNA splicing with tumor-suppressive activity in T-ALL.
2025-10-23 | SATB1 regulates TXNIP inhibiting invasion and infiltration in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis. Thioredoxin-interacting protein (TXNIP), a key protein, binds to thioredoxin and acts as a tumor suppressor in multiple cancers. However, its specific functions and mechanisms in T-ALL remain unclear. Here, CCK-8 and Transwell assays were used to assess its proliferation and invasiveness, with findings validated in a murine leukemia model. 4D proteomics combined with bioinformatics analyses were applied to elucidate its role in DNA damage repair. Guided by CHIP-seq results, we further validated the regulatory axis between Special AT-rich sequence binding protein 1 (SATB1) and TXNIP, as well as their involvement in T-ALL invasion, using CHIP-PCR and rescue assays. Our data demonstrated low expression of TXNIP in T-ALL patients. TXNIP significantly inhibited the proliferation and invasiveness of T-ALL cells and was involved in DNA damage response by suppressing MRN complex (MRE11-RAD50-NBS1) expression. We also identified SATB1 as a transcriptional regulator of TXNIP in Jurkat cells. Notably, TXNIP overexpression counteracted the pro-invasive effects induced by SATB1 knockdown in Jurkat cells (P < 0.05). In summary, TXNIP inhibits the proliferation and invasion of T-ALL, and impairs DNA damage repair processes. SATB1 positively regulates TXNIP, thereby suppressing the invasiveness of Jurkat cells.
cell therapies
2026-09-29 | Expression of miR-214 in Pediatric Acute Leukemia: Correlations with Leukemia Subtypes, Familial Predisposition, and Hepatitis B Virus Infection.
miR-214 dysregulation has been implicated in various cancers, yet its role in pediatric acute lymphoblastic leukemia (ALL) is not fully understood. This study evaluated miR-214 expression in newly diagnosed pediatric ALL patients and explored associations with leukemia subtypes, family history, and hepatitis B virus (HBV) infection. Bone marrow aspirates were collected from 44 pediatric ALL patients (26 B-ALL, 18 T-ALL) and five non-leukemic controls. qRT-PCR quantified miR-214 expression. Clinical data included HBV status and family history of hematologic malignancy. Relative expression levels were analyzed using 2-ΔΔCt and log₁₀ transformed for statistical analyses, including correlation and logistic regression models with interaction terms. The present study aimed to quantitatively evaluate the expression pattern of miR-214 in newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients compared with non-leukemic controls. In addition, the study sought to investigate whether miR-214 expression differs according to immunophenotypic subtype (B-ALL versus T-ALL) and to explore its potential associations with clinical and host-related factors, specifically family history of hematologic malignancy and hepatitis B virus (HBV) infection status. Furthermore, this study aimed to assess whether these variables exert interaction effects that may reflect context-dependent regulation of miR-214 in pediatric leukemogenesis. miR-214 expression was generally downregulated in ALL compared to controls, though differences were not statistically significant. B-ALL patients showed lower median expression than T-ALL, with the lowest levels observed in those with a positive family history. T-ALL patients exhibited broader expression variability, including marked upregulation in some cases. Exploratory regression models suggested differential effects of miR-214 based on HBV status and family history, but interaction terms did not reach statistical significance (p > 0.05). miR-214 expression in pediatric ALL appears to vary according to leukemia subtype and selected clinical factors, including family history and HBV infection. However, no statistically significant interaction effects were observed. These findings should be considered preliminary and warrant validation in larger, adequately powered cohorts to clarify the potential clinical relevance of miR-214 in leukemogenesis.
2026-09-29 | Lineage Plasticity-Mediated Resistance to CD7-Directed CAR-T Therapy in Relapsed/Refractory T-ALL/LBL.
CD7-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL). However, relapse remains a major obstacle. We generated a recyclable CD7 CAR-T cells (CD7 CARRecyclable) and conducted a phase I clinical trial to evaluate its safety and response in patients with R/R T-ALL/LBL (NCT05290155). Fourteen patients received CAR-T cells and were evaluable for safety and response. Immunophenotypic and molecular profiling were performed longitudinally to characterize relapse patterns. Robust CAR-T expansion was observed in 13 of 14 patients (92.9%). Peak CAR-T concentration (Cmax) reached 62,389.69 copies/μg DNA (range: 3,175.94-326,482.67) at median 12 days post-infusion (range: 10-21). All patients experienced hematologic toxicities, and cytokine release syndrome occurred in 71.4% of patients, predominantly grade 1-2. While ICANS developed in 2 patients (14.3%, grade 2 and 3) at day 8 and 28, respectively. Three out of four patients achieved measurable residual disease (MRD) -negative complete remission in bone marrow, while the objective response rate for extramedullary disease was 78.6%. With a median follow-up of 8.5 months, the estimated 6-month overall survival (OS) and progression-free survival (PFS) were 62.3% and 44.6%, respectively. Notably, lineage switch relapse occurred in two patients with ETP-immunophenotype following CAR-T therapy. These findings suggest that lineage plasticity might represent an under-recognized mechanism of resistance to CD7-directed CAR-T therapy in T-ALL/LBL, particularly in ETP-ALL/LBL, warranting further exploring.
2026-09-25 | Targeting the tumor, harboring the host: IL-7 receptor-targeted CARs to treat T-ALL
Chimeric antigen receptor (CAR) T cell therapy has fundamentally transformed clinical outcomes in B cell malignancies; however, the success story of CAR T cells has not yet extended to T cell acute lymphoblastic leukemia (T-ALL). A primary issue lies in the fundamental biology of the disease; most target antigens are shared between malignant T-ALL blasts and healthy T lymphocytes, including the CAR T cell product itself.
2026-08-24 | Efficacy, Safety, and Kinetics of Naturally Selected Anti‐ CD7 CAR ‐T Cell Therapy in T‐ ALL / LBL With CNS Leukemia
To the Editor, Central nervous system leukemia (CNSL) remains one of the most challenging manifestations of relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL).Despite intensive therapy, outcomes after CNS relapse remain poor and treatment options are limited [1-3].CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in R/R T-ALL/LBL, with complete remission (CR) rates approaching 90% [4][5][6][7].However, whether CD7 CAR-T cells can effectively traffic to and eradicate CNSL without excessive neurotoxicity remains poorly defined.
2026-07-20 | Research trends and hotspots of CAR-T cell therapy for acute lymphoblastic leukemia: A bibliometric analysis.
This study aims to analyze the global research patterns and emerging trends in CAR-T cell therapy for ALL through a bibliometric analysis. Publications were retrieved from the Web of Science Core Collection database. The bibliometric analysis utilized VOSviewer, CiteSpace, and the R package "bibliometrix" to visualize collaborations, keyword co-occurrences, and emerging research trends. A total of 844 articles from 253 journals by 6,459 authors across 44 countries were analyzed, showing an annual growth rate of 40.08%. The USA (372 articles, 38,065 citations) and China (275 articles, 5,636 citations) dominated research output. The University of Pennsylvania (353 articles), Memorial Sloan Kettering Cancer Center (170), and Children's Hospital of Philadelphia (131) were the most productive institutions, while Blood (41 articles) published the most articles. Stephan A. Grupp (38 articles, H-index = 30), Carl H. June (26 articles, H-index = 24), and Shannon L. Maude (25 articles, H-index = 20) were the most influential authors. Keyword analysis revealed five research clusters, including basic mechanisms, CAR design, population treatment integration, clinical outcomes, and toxicity management. Burst keyword analysis showed the evolution from basic science (2010-2013) to clinical translation (2014-2016), toxicity management (2017-2019), and recently to long-term outcomes and risk assessment (2020-2024), with "term follow-up" and "risk" as the only keywords with active bursts in 2024. This bibliometric analysis reveals that research on CAR-T therapy for ALL has progressed from foundational concepts to clinical implementation and now focuses on optimizing long-term outcomes and patient selection. Future research should prioritize biomarker development, next-generation CAR designs, and combination strategies to overcome persistence, toxicity, and resistance limitations in ALL treatment.
antibodies
2026-09-26 | Comparative In Vitro Apoptotic Activity of Two Chimeric Anti-CD99 Antibodies Recognizing Distinct CD99 Regions in T-ALL Models.
Background/Objectives: Therapeutic antibodies have become an important modality for cancer treatment; however, effective targeted antibody therapies for T-cell acute lymphoblastic leukemia (T-ALL) remain limited. CD99 is a promising therapeutic target due to its high expression in leukemic T cells and its capacity to transmit apoptotic signals. However, the efficacy of antibody-mediated apoptosis may depend on the CD99 region recognized by the antibody. This study compared the in vitro apoptotic activity of two chimeric anti-CD99 antibodies, ChAbMT99/1 and ChAbMT99/3, which recognize distinct regions of CD99 in T-ALL models. Methods: ChAbMT99/1 and ChAbMT99/3 were generated as human IgG1 antibodies. Antibody reactivity and binding site specificity were characterized using peptide-based ELISA. Binding to native CD99, apoptosis induction in two-dimensional (2D) Jurkat E6.1 and MOLT-4 suspension cultures and three-dimensional (3D) Jurkat E6.1-derived spheroid models, and cytotoxic effects on peripheral blood mononuclear cells (PBMCs) were assessed by flow cytometry. In vitro hematologic effects were assessed using hemagglutination and platelet aggregation assays. Results: ChAbMT99/1 and ChAbMT99/3 specifically recognized peptides corresponding to distinct CD99 regions, with peptide-binding EC50 values of 0.813 and 0.819 μg/mL, respectively. Both antibodies exhibited binding reactivity to native CD99 on the tested cells. Functionally, both antibodies induced Annexin V/7-AAD-defined cell death in both 2D and 3D T-ALL models compared with controls in a crosslinking-dependent manner. In contrast, both antibodies induced low levels of cell death (<10%) in bulk PBMCs, with no visible hemagglutination or platelet aggregation observed in samples from five selected donors under the stated assay conditions. Conclusions: Both chimeric anti-CD99 antibodies demonstrated in vitro apoptotic activity against T-ALL models despite recognizing distinct regions of CD99. These findings provide a rationale for further investigation of their other mechanisms of action to support the future development of CD99-targeted antibody therapy for T-ALL.
2026-09-16 | Daratumumab in Combination With High-Dose Cytarabine and Amsacrine as an Effective Salvage Therapy and Bridge to Allogeneic Hematopoietic Stem Cell Transplantation for Refractory T-Cell Acute Lymphoblastic Leukemia: A Case Report.
Patients with refractory or relapsed T-cell acute lymphoblastic leukemia (R/R T-ALL) have dismal outcomes. While immunotherapies are growing opportunities for B-cell ALL, targeted therapies for T-ALL remain limited. The CD38 antigen, steadily expressed on T-ALL blasts, represents a relevant therapeutic target. Daratumumab, an anti-CD38 monoclonal antibody routinely used in other hematologic malignancies, could be a promising treatment option for T-ALL. We report here the achievement of a third complete response with the combination of daratumumab, high-dose cytarabine (18 g/m2), and amsacrine in an 11-year-old patient with highly aggressive relapsed T-ALL, enabling subsequent allogeneic hematopoietic stem cell transplantation.
2026-09-15 | Targeting CD38 with bispecific antibody XmAb 18968 in patients with relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia.
CD38 is a transmembrane glycoprotein highly expressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to reduce non-selective activation of effector cells. In this phase 1 multicenter clinical trial, we evaluated the outcomes of XmAb18968 in adults with relapsed/refractory (RR) AML and T-ALL. Twenty-two patients with AML (n = 13) and T-ALL (n = 9) with a median age of 63 years (range 31-77) were enrolled. Prior lines of therapy (median 3, range 1-8) included venetoclax (77.3%), allogeneic HCT (22.7%), CD7 CAR-T cell therapy and daratumumab (11.1%). Grade ≥3 adverse events included anemia (14%), neutropenia (18%), and thrombocytopenia (14%). No grade ≥3 cytokine release syndrome or neurotoxicity was seen. Overall, 17 patients (AML = 11, ALL = 6) completed at least one cycle of therapy. Among 11 patients with RR-AML, one achieved partial remission (PR) and two achieved MRD negative complete remission (CR). In 6 patients with RR-T-ALL, 4 achieved meaningful improvement in disease burden with 1 clearance of MRD. Median OS was 8.5 months in AML and 8.7 months in T-ALL. XmAb18968 is safe and tolerable with encouraging preliminary efficacy, supporting further investigation of CD38 targeting therapies in this setting (NCT05038644).
2026-08-28 | Targeting CD38 in relapsed /refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy.
Relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) has poor outcomes and limited salvage options. Objectives: To evaluate the efficacy and safety of daratumumab-based therapy in R/R T-ALL/T-LBL. Systematic review of observational reports. Sixteen reports including 34 patients treated with daratumumab-based regimens were reviewed. Baseline characteristics, treatment patterns, response, MRD status, survival, allogeneic HSCT, and safety were descriptively synthesized. Complete remission was reported in 30/34 patients (88.2%), partial remission in 2/34 (5.9%), and no response in 2/34 (5.9%). Among complete responders with reported MRD status, 24/29 (82.8%) achieved MRD negativity. Median PFS was 10 months (range, 0.4-45), and median OS was 10 months (range, 1.5-45), although many values reflected last follow-up. Eighteen patients (52.9%) proceeded to allogeneic HSCT; 13/18 (72.2%) were alive at last follow-up. Infusion reactions occurred in 10 patients, mostly grade 1-2. Daratumumab-based therapy may induce remission and facilitate HSCT bridging in selected patients, but findings remain hypothesis-generating because evidence is mainly from case reports and small series.
2026-07-28 | T-ALL Elicits Robust T Cell Responses Despite Low Tumor Mutational Burden in multiple tissues with distinct TMEs 2267295
Abstract Introduction T-cell acute lymphoblastic leukemia (T-ALL) is a devastating pediatric malignancy arising from immature T cells. Despite improved survival rates, treatment still relies on intensive, toxic chemotherapy that fails to cure all patients. More effective and targeted therapies are urgently needed. Most immunotherapy efforts in T-ALL have focused on engineered cells (e.g., CAR T cells), while strategies leveraging patients’ pre-existing anti-tumor T cells remain largely unexplored. This is partly due to the assumption that T-ALL’s low tumor mutational burden (TMB) limits immunogenicity. However, our data challenge this paradigm using both murine models and patient samples. Methods We used murine transplantation models in which spontaneous T-ALL from CD45.2+ LN3 or LMO2 mice were transferred into immune-competent CD45.1+ congenic hosts, allowing distinction between malignant and host T cells. OTI/II and NUR77-GFP mice were used to assess TCR-dependent activation. Results T-ALL-bearing mice showed high frequencies of TOX+PD-1+ T cells, consistent with chronic, antigen-specific activation. Ex vivo stimulation revealed that PD-1+ T cells retained function, with increased IFN-γ production. To confirm TCR specificity, we transplanted T-ALL into OT-I/II mice (OVA-specific), where exhausted phenotypes were not induced–supporting a TCR-dependent mechanism. NUR77-GFP mice further confirmed high TCR signal strength in T cells from T-ALL-bearing hosts. Finally, treatment with aPD-1 or aCD40 improved survival, with enhanced benefit in combination. Conclusion These findings provide proof-of-concept that robust, functional, leukemia-specific T cell responses are mounted against T-ALL despite low TMB. This challenges existing dogma and supports the development of immunotherapy strategies that activate endogenous T cells. Ongoing studies aim to define how divergent tumor microenvironments regulate these responses and identify targets for rational combination immunotherapy. Funding Source na Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
small molecules
2026-09-29 | The Novel Organic Arsenical PZ2 Exhibits Potent Anti-T-ALL Activity via ROS-Dependent Apoptosis and GABARAPL1-Induced Autophagic Cell Death
Objective: T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological malignancy with poor overall prognosis. This study systematically evaluates the anti-leukemic therapeutic potential and underlying redox-driven mechanisms of PZ2, a novel organic arsenic compound, in T-ALL. Methods: The cytotoxicity of PZ2 against T-ALL cell lines and normal cells was assessed to determine its therapeutic window. RNA-seq was utilized to map transcriptomic alterations. Intracellular redox homeostasis, mitochondrial membrane potential (MMP), cell cycle, and apoptosis were evaluated using flow cytometry and fluorescence microscopy. Ultrastructural changes and key protein expressions were analyzed via TEM, RT-qPCR, and immunoblotting. In vivo efficacy was validated using a T-ALL cell-line-derived xenograft (CDX) mouse model. Results: PZ2 exhibited superior cytotoxicity and an improved safety profile compared to inorganic arsenic trioxide (ATO). Transcriptomic data indicated strong enrichment in apoptosis and autophagy–lysosome pathways. PZ2 induced profound mitochondrial oxidative stress, leading to ROS accumulation, MMP loss, and subsequent activation of caspase-dependent apoptosis—effects that were completely rescued by ROS scavengers. Furthermore, PZ2 triggered G2/M phase arrest and activated autophagic flux (upregulated GABARAPL1 and LC3-II, degraded p62). Notably, pharmacological inhibition of autophagy rescued PZ2-induced apoptosis, revealing a pro-death autophagic mechanism. In vivo, PZ2 significantly suppressed tumor growth and prolonged survival without overt systemic toxicity. Conclusions: PZ2 exhibits potent anti-T-ALL activity that may involve a dual mechanism: ROS-dependent mitochondrial apoptosis and pro-death autophagy potentially associated with GABARAPL1. This novel organic arsenical may represent a promising and potentially safer alternative for leukemia therapy, and these findings suggest a potential interplay between oxidative stress and autophagic cell death.
2026-09-25 | Case Report: Clinical response to TKI therapy in T-cell acute lymphoblastic leukemia with rare ABL1 rearrangement.
T-cell acute lymphoblastic leukemia (T-ALL) with ABL1 rearrangement is an extremely rare disease, and its clinical significance has not been precisely defined. We report the clinical characteristics of a pediatric patient with T-cell acute lymphoblastic leukemia harboring ABL1 rearrangement and the treatment response to tyrosine kinase inhibitor (TKI) therapy, providing a reference for clinical management with this subtype. A 3-year-old boy with T-ALL and ZBTB16::ABL1 fusion (RNA-seq) showed poor response to induction chemotherapy, failing remission at D33. Dasatinib (75 mg/m2/day) was added concurrently with CAM chemotherapy. At D90, morphological CR and flow-MRD negativity were achieved, though qPCR remained positive at 0.08%. Isolated CNS relapse occurred during Block III consolidation. Subsequent management included autologous CD7 CAR T-cell therapy and allogeneic HSCT; post-transplant evaluation confirmed sustained leukemia remission. However, the patient developed HHV-6 encephalitis and adenovirus hepatitis with hepatic failure; life-sustaining support was withdrawn at the family's request. The patient was discharged and lost to follow-up. This paper presents the second reported case to date of TKI treatment for T-cell acute lymphoblastic leukemia harboring the ZBTB16::ABL1 fusion. Following a review of the relevant literature on ABL1-rearranged T-ALL, we conclude that the accumulation of additional cases is essential to better characterize this rare molecular subtype and to guide evidence-based treatment decisions.
2026-09-17 | Metabolic reprogramming in T-cell acute lymphoblastic leukemia: Mechanisms of therapy resistance and clinical applications.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which therapy resistance remains a major cause of treatment failure and relapse. Increasing evidence indicates that metabolic reprogramming and metabolic plasticity can contribute to T-ALL persistence under therapeutic pressure, rather than reflecting a single uniform metabolic phenotype. In this review, we examine the reprogramming of glucose, amino acid, lipid, and nucleotide metabolism, as well as metabolic adaptations within the tumor microenvironment, and their associations with therapy resistance in T-ALL. We further discuss the regulatory roles of oncogenic signaling pathways and metabolism-epigenetics crosstalk in metabolic adaptation. Emerging metabolism-targeted strategies are also reviewed, with particular attention to their potential therapeutic vulnerabilities and the evidence supporting their use in different experimental and clinical contexts. Major barriers to clinical translation include metabolic heterogeneity, compensatory metabolic rewiring, and toxicity arising from metabolic dependencies shared with normal tissues. Future metabolic-directed therapies require precise metabolic subtyping guided by multi-omics approaches, the development of novel targeted drugs, and the implementation of rational combination therapies.
2026-09-10 | ENCERT: A Multisite Phase 1 Trial Using Everolimus in Combination With Nelarabine, Cyclophosphamide, and Etoposide in Relapsed T-Cell Lymphoblastic Leukemia/Lymphoma.
Relapsed and refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) remains a therapeutic challenge. Allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR) offers the only chance of cure, but effective modalities to achieve CR are limited. Activation of mTOR and PI3K pathways has been well described in T-ALL and monotherapy with mTOR inhibitors has shown efficacy signals used in relapsed disease. This multisite Phase 1 study evaluated the safety, tolerability, and anti-leukemic activity of everolimus with NEC chemotherapy (nelarabine, etoposide, and cyclophosphamide) among children and young adults with relapsed/refractory T-ALL/T-LL. Eight patients were enrolled to two dose levels (DLs) on this study and no dose-limiting toxicities were reported. Most adverse events related to therapy were expected and hematological. DL2 (n = 5) of everolimus at 5 mg/m2/day was the highest dose tested. The overall response rate (complete response + complete response with incomplete platelet recovery + partial response) was 75% (6/8) with 100% (5/5) responses in the T-ALL cohort and 33% (1/3) responses in T-LL cohort. All six patients who obtained a PR or greater proceeded to receive HSCT as consolidation therapy. Two of the six patients transplanted are alive today with two deaths related to progressive disease and two related to veno-occlusive disease post transplantation. This study demonstrates safety with a combination of everolimus and NEC chemotherapy. Given the observed tolerability and efficacy of everolimus with NEC in this small cohort of patients, this combination should be further evaluated in larger phase 2/3 clinical trials. ClinicalTrials.gov identifier: NCT03328104.
2026-08-28 | Venetoclax with azacitidine and dexamethasone: Non-cytotoxic induction therapy for T-cell leukemia and mixed-phenotype leukemia.
T-lineage acute leukemias are aggressive malignancies for which treatment options are limited. This study evaluated the efficacy and safety of a non-cytotoxic regimen combining venetoclax, azacitidine, and dexamethasone (VAD) as first-line induction therapy for T-cell acute lymphoblastic leukemia (T-ALL) and T/myeloid mixed-phenotype acute leukemia (T-Myeloid MPAL). We retrospectively analyzed the clinical parameters and survival data of 11 patients with newly-diagnosed T-ALL or T-Myeloid MPAL who received the VAD regimen. The complete remission (CR) rate and adverse events were assessed. Kaplan-Meier curves were constructed to evaluate survival outcomes. Among 11 patients (7 with early T-cell precursor [ETP] ALL, 2 with T-Myeloid MPAL, and 2 with non-ETP T-ALL), the overall CR rate after one cycle of VAD therapy was 90.9%, with 45.5% achieving measurable residual disease (MRD) negativity by flow cytometry. The historically poor-prognosis ETP-ALL subgroup showed an 85.7% CR rate (6/7), while both T-Myeloid MPAL cases attained MRD negativity. No tumor lysis syndrome or treatment-related mortality occurred. Over a median follow-up of 358 days, all 5 patients who received transplantations remained relapse-free. The VAD regimen demonstrated a high response rate and favorable safety, enabling effective transplantation bridging with avoidance of conventional cytotoxic therapy.
oligonucleotides
2025-10-22 | Characterization of a PRKCE::ETV6 fusion as a potential oncogenic driver in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by mutation accumulation during hematopoiesis. The characterization of chromosomal abnormalities may provide significant insights into genetic mechanisms of malignant transformation in hematopoietic cells. However, T-ALL is genetically very heterogenous and driving mutations as well as clonal markers for the assessment of minimal residual disease are not always identifiable. Hence, there is a clinical need to further refine the genetic landscape of T-ALL including previously unrecognized fusion partners of commonly translocated genes in T-ALL of childhood. In this study, we screened n = 229 T-ALL cases by our targeted genomic capture high-throughput sequencing (gc-HTS) approach. In total, we identified n = 60 gene–gene fusions, present in n = 57 (25%) of the patients. Nine rare or even unrecognized translocations were identified and validated. Furthermore, owing to its interesting chromosomal structure, we studied the oncogenic potential of the complex rearrangement of chromosome 2 and 12, found in a near-early T-cell progenitor (ETP) ALL that leads to the fusion events PRKCE::ETV6 and ETV6::INO80D. Exogenous expression of PRKCE::ETV6 in Ba/F3 pro-B and D1 T-cells caused interleukin-independent proliferation and enhanced survival upon interleukin withdrawal, respectively. Our study underlines the heterogenous mutational landscape in T-ALL. The previously unrecognized PRKCE::ETV6 resulting from a complex rearrangement involving chromosome 2 and 12 demonstrated transforming potential in cytokine-dependent cellular models support the notion of a driver mutation in near ETP-ALL. Our data reconfirm the relevance of ETV6-fusion proteins in the pathogenesis of undifferentiated T-ALL. Importantly, genomic breakpoints at the ETV6 locus represent potentially robust MRD markers for (near) ETP-ALL that lack IG/TR rearrangements. The online version contains supplementary material available at 10.1186/s40348-025-00208-x.
2024-11-25 | Aptamer sgc8-Modified PAMAM Nanoparticles for Targeted siRNA Delivery to Inhibit BCL11B in T-Cell Acute Lymphoblastic Leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease with limited targeted therapy options. Overexpression of B-cell lymphoma/leukemia 11B is frequently observed in T-ALL and contributes to leukemogenesis. Knockdown of BCL11B inhibits T-ALL cell proliferation and induces apoptosis, making it a potential therapeutic target. However, the clinical application of siRNA therapies is hindered by challenges such as poor delivery efficiency and limited clinical outcomes. We developed a targeted delivery system for BCL11B siRNA (siBCL11B) using generation 5 polyamidoamine (G5-PAMAM) dendrimers conjugated with the sgc8 aptamer, which specifically binds to the T-ALL cell membrane protein PTK7. This nanoparticle, designated G5-sgc8-siBCL11B, was designed to selectively deliver siRNA to T-ALL cells. In vitro and in vivo experiments were conducted to evaluate its therapeutic efficacy and safety. We demonstrate that sgc8-conjugated siBCL11B nanoparticles selectively and efficiently target BCL11B-overexpressing T-ALL cells, significantly inhibiting cell viability and promoting apoptosis while exhibiting minimal impact on the viability of normal T cells. In T-ALL mouse model studies, G5-sgc8-siBCL11B and G5-siBCL11B significantly inhibited the progression of T-ALL in vivo, extending the survival of mice compared to the control (CTR), G5, and G5-sgc8 groups. Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993). The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.
2024-04-12 | Limited dsRNA editing impedes leukemia stem cells.
Understanding the mechanisms underlying the generation and maintenance of leukemia stem cells (LSCs) is crucial for the development of effective therapies against T cell acute lymphoblastic leukemia (T-ALL). In a recent study, Rivera et al. discovered that elevated adenosine deaminase acting on RNA (ADAR)-1-mediated RNA editing is a distinguishing feature of T-ALL relapse, and that ADAR1 suppresses apoptosis triggered by the double-stranded (ds)RNA-sensing pathway.
2024-03-04 | Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.
Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T-ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, we uncover that the cell-intrinsic level of MDA5 dictates the dependency on the ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.
2024-01-08 | Involvement of TAL1-microRNA Axis in the Progression of T-cell Acute Lymphoblastic Leukemia
The T-cell acute lymphoblastic leukemia 1 (TAL-1) transcription factor is crucial for T-cell differentiation, but the ectopic expression in 30% of cases can disrupt normal differentiation, and promote cancer progression. This can be due to microRNA (miRNA) dysregulation or other oncogenes. The present study covers articles related to T-cell acute lymphoblastic leukemia (T-ALL), TAL-1 and miRNA, which were published in the English language from 1994 to 2023. After analyzing the research, it is evident that the TAL-1 overexpression is associated with alterations in several miRNAs, which encompass both those that suppress tumors, and those that stimulate cell growth. The interplay between TAL-1 and miRNAs exhibits diverse dynamics. For example, specific miRNAs, such as miR-223, interact with the TAL-1 gene promoter, resulting in its upregulation. In contrast, the miR-17-92 cluster indirectly influences the stability of the TAL-1 transcription complex. Typically, the interaction between TAL-1 and its associated miRNAs follows a unidirectional pattern, in which miRNAs that target TAL-1 are downregulated, leading to elevated TAL-1 levels. Nevertheless, TAL-1 exhibits a bidirectional relationship with miR-223, in which each positively affects the expression of the other. In addition, there is a cooperative interaction between miR-146-5b and TAL-1. Unlike miR-223, TAL-1 reduces the expression of miR-146-5b, thereby inhibiting tumor growth. Individuals with T-ALL, who experience disruptions in the TAL-1 and miRNA network, often face a poor prognosis, and their tumors tend to be larger. In conclusion, delving deeper into the network of miRNAs associated with TAL-1 in T-ALL offers a novel perspective on cancer prognosis and the development of improved diagnostic and treatment strategies.
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2026-05-11 | CRISPR Genome Editing and the Future of Leukaemia Immunotherapy.
Leukaemia presents ongoing therapeutic challenges due to relapse and toxicity associated with standard treatments. By enabling more targeted and safer therapies, CRISPR genome editing is emerging as a powerful tool to address these issues. We review current literature on CRISPR technologies in leukaemia immunotherapy, focussing on studies involving four key antigens commonly targeted in leukaemia: CD33, CD7, CD45 and CD19. We trace the evolution of CRISPR technologies from conventional CRISPR-Cas9 to base editing, highlighting how CRISPR platforms are being repurposed to enhance efficacy and clinical safety. Key studies targeting CD33 demonstrate how editing strategies can enable safer acute myeloid leukaemia (AML) therapies by reducing off-tumour toxicity; those addressing CD7 show how base editing prevents T-cell fratricide in T-cell acute lymphoblastic leukaemia (T-ALL) immunotherapy; studies focusing on CD45 illustrate how targeted editing facilitates universal CAR T-cell therapy; and clinical trials on CD19 support the feasibility of "off-the-shelf" treatments against paediatric B-cell acute lymphoblastic leukaemia (B-ALL). While base editing excels in precision and functional preservation, CRISPR-Cas9 remains preferred when complete gene knockout is desired. As off-tumour toxicity and fratricide are addressed, the future clinical impact of these technologies is poised to expand.
2026-04-03 | PERSONALIZED MULTI-EPITOPE PEPTIDE VACCINE DESIGN TARGETING NOTCH1 MUTATIONS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL): A COMPREHENSIVE IMMUNOINFORMATICS ANALYSIS
Large-scale somatic mutation data from COSMIC v97, GenomePaint (St. Jude Cloud), and TARGET/TCGA (N = 1,392 T-ALL samples) were integrated to identify high-frequency hotspot mutations at exons 26–27. Five MHC class I neoepitopes were predicted and stringently filtered using NetMHCpan-4.1, HLAthena, and NetMHCstabpan against a Vietnamese-prevalent HLA allele panel. A multicomponent vaccine construct was assembled incorporating the molecular adjuvant CTB, two universal T-helper epitopes (P2/P30), three MHC class II helper epitopes from NOTCH1 and RHEB, one linear B-cell epitope from NOTCH1, and a clinically validated modified WT1 epitope (CYTWNQMNL). The construct underwent comprehensive evaluation of physicochemical and immunological properties, 3D structure prediction (AlphaFold2/RoseTTAFold2), molecular docking (AutoDock Vina, PatchDock/FireDock), immune simulation (C-ImmSim), and codon optimization (JCat).
2026-04-02 | CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-Cell Acute Lymphoblastic Leukemia (T-ALL) Therapy.
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with limited targeted therapies. CD28, a costimulatory receptor aberrantly overexpressed on T-ALL cells, presents a promising underexplored therapeutic target. In this study, we developed an enzyme-responsive self-assembling peptide, SAp-CD28, designed to target CD28 and undergo receptor-mediated self-assembly in the tumor microenvironment. Upon dephosphorylation by overexpressed phosphatases, SAp-CD28 transitions from an α-helix to a β-sheet/β-turn rich structure, facilitating the formation of nanooligomers that engage CD28 and activate cytotoxic pathways. Transcriptomic and biochemical analyses reveal that SAp-CD28 induces a profound dysregulation of CD28 downstream signaling, characterized by the suppression of the PLCγ and Akt pathways. These signaling perturbations lead to oxidative stress and disruption of intracellular calcium homeostasis, resulting in calcium overload, calpain activation, and cytoskeletal collapse. Besides, confocal imaging suggested that the peptide self-assembly can enter the nucleus and disrupt it. In Jurkat xenograft models, SAp-CD28 demonstrated potent antitumor activity, and its combination with cytarabine resulted in near-complete tumor suppression, highlighting its potential for T-ALL treatment. This work introduces a CD28-targeted, enzyme-activated nanotherapeutic strategy that synergizes biochemical and mechanical mechanisms to selectively eliminate T-ALL cells. This multi-mechanistic tumor-killing strategy can also be extended to inspire therapeutic approaches for other diseases.
2026-01-15 | QKI dysregulation induces extensive splicing changes in T-cell acute lymphoblastic leukemia.
Understanding the molecular mechanisms underlying T-cell acute lymphoblastic leukemia (T-ALL) is essential for developing more effective therapeutic strategies. Despite therapeutic advances, the role of RNA-binding proteins in the pathogenesis of T-ALL remains poorly understood. Here, we investigate the RNA-binding Quaking protein (QKI), identifying it as a key regulator of splicing with tumor-suppressive properties in T-ALL. Through the analysis of two independent pediatric T-ALL cohorts, we demonstrate that QKI expression is frequently reduced in T-ALL, particularly within the HOXA subtype, and this reduction correlates with poor overall and event-free survival. Using T-ALL cell lines, we show that QKI depletion induces widespread splicing alterations, with numerous events corroborated in patient samples. Transcriptome profiling indicates that QKI downregulation leads to broad changes in gene expression, notably affecting pathways related to cell cycle progression, cholesterol homeostasis, and epithelial-mesenchymal transition. Functional assays demonstrate that QKI overexpression in T-ALL cells significantly reduces cell proliferation, induces G0/G1 cell cycle arrest, and limits leukemia progression and dissemination, ultimately improving survival in xenograft models. Together, these findings provide compelling evidence that QKI functions as a regulator of RNA splicing with tumor-suppressive activity in T-ALL.
2025-10-23 | SATB1 regulates TXNIP inhibiting invasion and infiltration in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis. Thioredoxin-interacting protein (TXNIP), a key protein, binds to thioredoxin and acts as a tumor suppressor in multiple cancers. However, its specific functions and mechanisms in T-ALL remain unclear. Here, CCK-8 and Transwell assays were used to assess its proliferation and invasiveness, with findings validated in a murine leukemia model. 4D proteomics combined with bioinformatics analyses were applied to elucidate its role in DNA damage repair. Guided by CHIP-seq results, we further validated the regulatory axis between Special AT-rich sequence binding protein 1 (SATB1) and TXNIP, as well as their involvement in T-ALL invasion, using CHIP-PCR and rescue assays. Our data demonstrated low expression of TXNIP in T-ALL patients. TXNIP significantly inhibited the proliferation and invasiveness of T-ALL cells and was involved in DNA damage response by suppressing MRN complex (MRE11-RAD50-NBS1) expression. We also identified SATB1 as a transcriptional regulator of TXNIP in Jurkat cells. Notably, TXNIP overexpression counteracted the pro-invasive effects induced by SATB1 knockdown in Jurkat cells (P < 0.05). In summary, TXNIP inhibits the proliferation and invasion of T-ALL, and impairs DNA damage repair processes. SATB1 positively regulates TXNIP, thereby suppressing the invasiveness of Jurkat cells.
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