RARE DISEASE
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Drug discovery
8
drugs
With orphan designations
Overview
Anaplastic large cell lymphoma (ALCL) is a rare CD30-positive T-cell non-Hodgkin lymphoma with distinct subtypes: systemic (ALK-positive or ALK-negative), primary cutaneous, and breast implant-associated (BIA-ALCL). ALK-positive cases, more common in children/young adults, have favorable prognoses with anthracycline-based chemotherapy (e.g., CHOP/CHOEP). ALK-negative disease, prevalent in older adults, has poorer outcomes. Brentuximab vedotin (anti-CD30) and stem cell transplantation are key for relapsed/refractory cases. BIA-ALCL is linked to textured implants and typically resolves with implant/capsule removal [1][6][7][12][18].
Therapies
First-line: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) ± etoposide (CHOEP) for ALK-positive [1][8][12].
Targeted therapy: Brentuximab vedotin (CD30-directed) for relapsed/refractory or frontline ALK-negative cases [1][12][14].
Advanced disease: Stem cell transplantation (autologous/allogeneic); BIA-ALCL requires implant removal with capsulectomy [3][8][18].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,420 drug discovery papers about Anaplastic large cell lymphoma, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,420 drug discovery papers about Anaplastic large cell lymphoma, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-05-14 | Chimeric Antigen Receptor T‑Cell Therapy Targeting Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30) for Relapsed or Refractory Anaplastic Large Cell Lymphoma: Rationale, Strategies, and Emerging Clinical Evidence.
Chimeric Antigen Receptor (CAR) T-cell therapy has fundamentally altered the treatment paradigm for relapsed or refractory (R/R) B-cell malignancies. However, translating this success to T-cell lymphomas has been impeded by a critical biological barrier: fratricide. This process describes the self-destruction of therapeutic T-cells caused by their shared expression of target antigens, such as Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30), following activation. Anaplastic Large Cell Lymphoma (ALCL), characterized by its uniform and high-level expression of CD30, represents both an ideal candidate for this approach and a significant scientific challenge. This comprehensive review begins by outlining the established landscape of approved CD19- and BCMA-directed CAR-T therapies to provide context. It then focuses specifically on the application of anti-CD30 CAR-T therapy for ALCL, examining the molecular mechanisms that drive fratricide. We explore the innovative engineering and manufacturing strategies developed to overcome this obstacle, including ultrarapid production protocols, the selection of virus-specific T-cells, and precise genetic disruption of the TNFRSF8 gene using CRISPR/Cas9 technology. An analysis of early phase clinical trial data reveals encouraging efficacy, with high rates of durable complete responses observed even in heavily pretreated patients who have failed brentuximab vedotin therapy. Furthermore, these initial studies report a remarkably favorable safety profile, characterized by a near absence of severe cytokine release syndrome and neurotoxicitya feature that distinctly contrasts with CD19-directed therapies. While these findings are promising, it is essential to acknowledge that the current evidence base remains preliminary, derived from small, heterogeneous patient cohorts and requiring validation in larger, more definitive trials with extended follow-up. By successfully addressing the challenge of fratricide, anti-CD30 CAR-T therapy holds the potential to become a transformative and potentially curative option for patients with R/R ALCL and may offer a valuable blueprint for developing effective immunotherapies against other T-cell malignancies.
2026-05-08 | Autologous and allogeneic hematopoietic cell transplantation in children and adults with high-risk anaplastic large cell lymphoma.
Both autologous and allogeneic hematopoietic cell transplantation (HCT) have been used to treat high-risk anaplastic large cell lymphoma (ALCL) that has failed conventional chemotherapy. However, many patients are not able to fully eradicate disease prior to HCT, making the role of either form of HCT unclear. The aim of this study was to collect characteristics and outcomes of patients who underwent either autologous and/or allogeneic HCT and determine the role that disease status at HCT plays in overall survival (OS). To address this, we collected data on 41 patients with ALCL that underwent autologous (n=24) and/or allogeneic (n=17) HCT at our center between 1997-2020. The 5-year estimated progression-free survival (PFS) and OS for the autologous HCT group was 40% (95% confidence interval, 20-59%) and 53% (31-71%), while for the allogeneic HCT group it was 65% (38-92%) and 65% (38-82%), respectively. For transplants performed in 2009 or later, 5-year OS was 91% (51-99%) in the allogeneic HCT group, and 51% (23-73%) in the autologous HCT group. Notable was that for those who entered transplant with detectable disease, 5-year OS was 50% (15-77%) with allogeneic HCT whereas it was 27% (7-54%) for autologous HCT. These data confirm that HCT is a potentially curative therapy, and allogeneic HCT may have a survival advantage over autologous HCT when there is detectable disease prior to HCT.
2026-04-03 | Abstract 5615: ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma
Abstract Introduction: Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL) is a rare subtype of T-cell lymphoma driven by nucleophosmin 1 (NPM1)-ALK fusion protein. Treatment with standard chemotherapy or ALK tyrosine kinase inhibitor crizotinib is highly effective; however, a significant portion of patients still experience relapses or refractory disease, highlighting the need for innovative therapeutic options. Our group has recently identified two ALK-specific T cell receptors targeting the human ALK peptide RPRPSQPSSL presented by HLA-B*07:02 (B7) and demonstrated specific and robust anti-tumor activity of ALK.TCR-T cells (ALK.TCR-T) in ALK+ non-small cell lung cancer [Mecca et al, Cancer res, 2024]. In this work, we aimed to address the efficacy of ALK.TCR-T in multiple models of ALK+ ALCL. Methods: Two ALK-specific TCRs were retrovirally transduced into human CD3+ T cells to generate ALK.TCR-T1 and ALK.TCR-T2. The anti-tumor activity of ALK.TCR-T was tested both in vitro and in vivo against a panel of crizotinib-sensitive and crizotinib-resistant ALK+ ALCL models. The specificity of peptide-MHC recognition was evaluated by employing ALK+/B7+, ALK+/B7-, and ALK-/B7+ cells. For in vivo studies, NSG mice were injected intravenously with ALK+ ALCL cell lines, and, after engraftment, treated with ALK.TCR-T, alone or in combination with crizotinib. Mice received 50mg/kg crizotinib by oral gavage for 10 days. Tumor growth was evaluated weekly by bioluminescence imaging. Results: In vitro killing assays demonstrated that both ALK.TCR-T selectively recognize and eliminate 80-100% of ALK+/B7+ ALCL, while no killing occurred in ALK+/B7- or ALK-/B7+ models, confirming that ALK.TCR-T specifically target the ALK peptide RPRPSQPSSL presented by HLA-B*07:02. Moreover, ALK-TCR-T were equally effective in killing crizotinib-resistant ALCL cells, independently of the mechanism driving the resistance to crizotinib. Interestingly, the combination of ALK.TCR-T and crizotinib potentiated the killing of crizotinib-sensitive ALK+ ALCL even at unfavorable E:T ratios (1:5 and 1:10).A single treatment with ALK.TCR-T significantly slowed tumor growth in an ALK+/B7+ systemic tumor model and increased the survival of mice, compared to treatment with irrelevant TCR-T cells. The combined treatment with ALK.TCR-T and crizotinib resulted in a further enhancement of tumor regression and mouse survival, with 50% (5/10) mice with no evidence of tumor 40 days after ALK.TCR-T injection. Conclusions: We demonstrated that ALK.TCR-T show specific and potent anti-tumor activity against multiple ALK+ ALCL models both in vitro and in vivo. The combination of ALK.TCR-T and crizotinib further potentiate the ability of ALK.TCR-T to control tumor growth and extend the survival of mice. These results lay the basis for developing a novel immunotherapy strategy for patients with ALK+ ALCL. Citation Format: Simone Piane, Carmen Mecca, Nirmala Tilija Pun, Ana Azambuja, Luca Alessandri, Phuc Bao Nguyen, Elisa Bergaggio, Gabriele Saccu, Alessandro Gasparetto, Haley Ohlson, Claudia Voena, Marcos Simoes-Costa, Roberto Chiarle. ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5615.
2026-01-21 | Positionally Stable Smooth Implants: An In Vivo Submuscular Model.
Following the voluntary recall of certain textured implants due to recognized association with BIA-ALCL, plastic surgeons lost the major benefit of textured surfaces-positional stability. We have engineered a novel smooth-surface breast implant design featuring small millimeter-dimension cylindrical surface wells that promote tissue ingrowth and stabilize the implant. These Positionally Stable Smooth Implants (PSSI) previously demonstrated superior positional stability versus smooth implants (and comparable to textured) in a subcutaneous in vivo model. Here, we investigate PSSI in a submuscular model. Hemispherical miniature breast implants were fabricated with polydimethylsiloxane. PSSI implants featured wells 2mm wide by 1mm deep with 26, 52, or 70 wells/implant. Miniature smooth and textured implants served as controls. Six implants per group were placed under bilateral latissimus dorsi muscles of female Sprague-Dawley rats. Implant position was evaluated at 2, 4, 8, and 12 weeks, then explanted. Over 12 weeks, PSSI exhibited significantly less rotation than smooth implants (p<0.001) and comparable to that of textured implants. Textured and some PSSI capsules had significantly lower collagen density and smooth muscle actin expression compared to smooth implants (p<0.05). PSSI and smooth capsules had lower pro-inflammatory M1 macrophage expression and a lower M1/M2 macrophage ratio than textured capsules (p<0.01). PSSI implants demonstrated significantly increased rotational stability and reduced collagen density and myofibroblast presence compared to smooth implants, as well as significantly decreased expression of pro-inflammatory macrophages compared to textured implants. These data suggest a promising alternative to texturing for providing positional stability of implants in the submuscular plane.
2025-11-29 | Emerging therapeutic strategies for CD30-positive lymphomas.
The antibody-drug conjugate brentuximab vedotin (BV) has significantly improved outcomes for CD30-expressing lymphomas. The ECHELON-2 trial established BV combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as a frontline standard for systemic anaplastic large cell lymphoma, demonstrating superior survival over the traditional CHOP regimen. Despite this progress, the limitations of a universal BV + CHP standard are increasingly apparent, and the therapeutic landscape is rapidly diversifying. This review critically evaluates the evidence supporting BV + CHP, including methodological considerations of the ECHELON-2 trial, and explores the expanding arsenal of novel therapies. We assess alternative strategies, such as BV-based combinations with immunotherapies or alternative chemotherapies, the integration of other targeted agents, and the transformative potential of advanced cellular treatments like anti-CD30 chimeric antigen receptor (CAR)-T cell therapy for relapsed/refractory disease. The collective evidence signals a paradigm shift from a one-size-fits-all approach toward personalized, precision-driven strategies aimed at maximizing efficacy, minimizing toxicity, and improving long-term quality of life for patients with CD30-positive lymphomas.
antibodies
2026-08-15 | ALK-negative anaplastic large cell lymphoma in pediatric and adolescent patients: a mini-review.
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.
2026-08-01 | Intravenous pharmacologic ascorbate as a redox modulator and chemosensitizer in targeted Cancer therapies.
Intravenous pharmacologic ascorbate represents a re-emerging oncologic adjunct that exploits concentration-dependent pro-oxidant effects to selectively induce oxidative stress in malignant cells while preserving normal tissue. Supported by recent clinical data in metastatic pancreatic ductal adenocarcinoma, where high-dose ascorbate combined with gemcitabine and nab-paclitaxel has improved survival outcomes, this review proposes a broader therapeutic paradigm. This paper presents a hypothesis-driven translational perspective that synthesises current mechanistic evidence with a novel therapeutic proposal. Using Brentuximab Vedotin-based therapy for CD30-positive lymphomas as a representative model, we delineate the multi-mechanistic potential of intravenous pharmacologic ascorbate to enhance targeted treatment regimens. Intravenous pharmacologic ascorbate may act as both a redox disruptor and chemosensitizer-amplifying antibody-drug conjugate cytotoxicity through oxidative stress potentiation, apoptotic enhancement, and tumour microenvironment modulation. While preclinical evidence from related chemotherapy contexts suggests potential for synergistic interactions, direct evidence for this specific combination is currently lacking, and the mechanisms discussed remain hypothetical until validated in appropriate models. Notably, the redox-modulating properties of intravenous pharmacologic ascorbate could theoretically address common resistance pathways in cancer, such as the upregulation of endogenous antioxidant defences. Furthermore, emerging data suggests intravenous pharmacologic ascorbate may also influence epigenetic regulation in cancer cells through modulation of α-ketoglutarate-dependent dioxygenases, including ten-eleven translocation enzymes and histone demethylases, potentially reversing hypermethylation-associated silencing of tumour suppressor genes. This paper advocates for preclinical validation followed by well-designed phase II clinical trials to evaluate the safety, efficacy, and pharmacodynamics of intravenous pharmacologic ascorbate combined with targeted therapies. If the hypothesised benefits are confirmed, this approach could position intravenous pharmacologic ascorbate as an accessible, low-toxicity adjunct capable of improving long-term outcomes and quality of life for patients with aggressive malignancies.
2026-07-31 | Breast implant associated anaplastic large cell lymphoma is a heterogeneous T cell disease with active pro-tumour cross-talk and immune suppression.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T cell lymphoma in women with textured implants. Little is known about the cell of origin (COO) and whether the tumour immune microenvironment (TIME) is critical for BIA-ALCL survival. Single-cell RNA sequencing revealed BIA-ALCL cells were heterogeneous with unique gene profiles per patient and signature genes BATF3, SERPINS, TNFSFR8, and IL2RA. The COO is a CD4+ or CD8+ memory T cell identified through rearranged TCR and gene expression. The BIA-ALCL TIME included distinct myeloid clusters, dendritic cells (DCs), and monocytes, which may support lymphoma cells. Cytokines IL-13, IL-10, TNF and secretory PDL1 were increased in BIA-ALCL seroma, indicating an immunosuppressive TIME. Interactome analysis revealed a complex network among lymphoma cells, dominated by IL-13, IL-10, and TNF members. Endogenous CD8+ T cells exhibit higher checkpoint expression than benign seromas. No clonal relationship exists between BIA-ALCL and endogenous T cells. Tissue-archetype and gene-expression analysis revealed T-cell exclusion and immunosuppressive TIME in invasive disease. In summary, BIA-ALCL cells are diverse with markedly different TIME across stages. The TIME provides immunosuppressive signals to activated/exhausted T cells and homeostatic signals that promote BIA-ALCL proliferation. These new findings may offer novel therapeutic targets for advanced disease patients.
2026-07-28 | CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma.
Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell lymphomas (T-NHLs) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. While case reports and individual Anaplastic Large Cell Lymphoma (ALCL) cases enrolled in T-NHL trials demonstrated favourable responses to ICI, hyperprogression was observed in other T-NHL subtypes. We therefore utilized a syngeneic mouse model of ALK+ ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and NK cells. Innate and adaptive immune cell infiltration was confirmed on a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in approximately 50% of treated animals. Mechanistically, PD-L1 blockade reversed Treg-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby prolonging survival significantly. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced anti-tumour responses in murine ALCL. CD4+ T cells of non-responder animals exhibited an exhausted phenotype and a transcriptomic Th22-like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune-evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.
2026-07-23 | ALK-Negative Systemic Anaplastic Large Cell Lymphoma with Cutaneous Involvement Initially Mimicking Primary Cutaneous Disease: A Case Report.
Anaplastic large cell lymphoma (ALCL), a subgroup of T-cell non-Hodgkin's lymphoma, is a relatively uncommon malignancy with a highly variable prognosis. Systemic ALK-negative status and high Ki-67 expression are generally associated with poor outcomes in ALCL patients. Systemic ALK-negative ALCL presenting initially with cutaneous involvement is rare, with only a few cases reported in the literature. The aggressive clinical course of systemic ALK-negative ALCL with cutaneous lesions contrasts sharply with the indolent behavior of primary cutaneous ALCL (C-ALCL). Accurate distinction requires integration of histopathological and immunophenotypic findings. In particular, negativity for cutaneous lymphocyte antigen (CLA) is a useful discriminator, as primary C-ALCL typically expresses CLA while systemic cases often do not. Accumulating more clinical data is essential to better characterize this entity and guide therapeutic decisions. Here, we report a case of aggressive ALK-negative systemic ALCL that presented with cutaneous nodules as the initial manifestation, clinically mimicking primary C-ALCL.
small molecules
2026-07-31 | Arsenic trioxide promotes a glue‑like interaction to drive STUB1-mediated NPM-ALK degradation in ALK+ ALCL.
The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion constitutively activates ALK tyrosine kinase, driving oncogenesis in anaplastic large cell lymphoma (ALCL). While arsenic trioxide (ATO) exhibits therapeutic potential, its precise mechanism remains elusive, limiting clinical application. Here, we used a combined approach of E3 ligase library screening, ATO chemical proteomics, and NPM-ALK immunoprecipitation-mass spectrometry to reveal that ATO regulates NPM-ALK stability via the E3 ligase STUB1. Clinically, high STUB1 expression correlates with improved survival, identifying it as a candidate favorable prognostic biomarker in NPM-ALK+ ALCL. Mechanistically, ATO promotes a glue‑like interaction that stabilizes the ternary complex of STUB1 and NPM-ALK, promoting ubiquitination at K174 and subsequent proteasomal degradation. Furthermore, structural modeling, domain mapping, and point mutations support a proposed arsenic-dependent interaction model involving STUB1 Cys83, Cys103, and NPM-ALK Cys599, which may modulate the STUB1-NPM-ALK interface and enhance their interaction, thereby promoting ubiquitin-mediated degradation. Crucially, we demonstrate that STUB1 overexpression or pharmacological activation using the FDA-approved cardiac glycoside Deslanoside synergizes profoundly with ATO to inhibit tumor growth both in vitro and in vivo. These findings provide novel mechanistic insight into ATO's action in NPM-ALK+ ALCL and reveal new therapeutic strategies and candidate prognostic biomarkers for patient management.
2026-07-01 | Endobronchial anaplastic large cell lymphoma presenting as unilateral white-out lung: Successful chemotherapy in an adolescent: A case report
Abstract White-out lung encountered in the pediatric emergency room can lead to life-threatening respiratory failure. A 16-year-old boy presented with “white-out” lung on his chest X-ray. He needed mechanical ventilation for respiratory failure. Bronchoscopy revealed that his left main bronchus was completely blocked by a vascular mass. A biopsy confirmed anaplastic large-cell lymphoma (ALCL). After starting chemotherapy, he showed dramatic improvement within 5 days, was successfully extubated, and transitioned to care under the pediatric hematology–oncology team. This case report highlights endobronchial ALCL, a rare cause of “white-out lung,” diagnosed via prompt bronchoscopy and favorable outcome with a short course of chemotherapy.
2026-06-25 | [A patient with dizziness and gait instability - a diagnostic challenge].
A 58-year-old patient presented with progressive cerebellar ataxia and lymphocytic pleocytosis with normal MRI findings. Detection of Anti-TR(DNER) antibodies led to the diagnosis of paraneoplastic encephalitis. Tumor workup revealed anaplastic large cell lymphoma. Combined immunotherapy and chemotherapy resulted in clinical stabilization.
2026-06-05 | CircRNAs derived from the tyrosine phosphatase PTPN22 impact chemosensitivity in ALK-positive T-cell lymphomas.
Anaplastic large cell lymphoma (ALCL) is a subtype of T-cell non-Hodgkin lymphoma (NHL), classified into ALK(+) and ALK(-) subtypes, based on translocations of the ALK gene. ALK(+) ALCL have a favorable prognosis with polychemotherapy, yet some patients develop early chemoresistance, leading to treatment failure. The molecular mechanisms underlying this resistance remain poorly defined. Circular RNAs (circRNAs) have recently emerged as regulators of drug resistance in cancer, but their role in T-NHLs is largely unexplored. A comprehensive analysis of circRNA expression was performed here in primary ALK(+) ALCL biopsies. RNA-Seq identified 12 circRNAs associated with early relapse, including isoforms from the PTPN22 gene (circPTPN22), significantly upregulated in relapsed patients. Functional analyses showed that the ALK/STAT3 signaling pathway regulates circPTPN22 expression, linking oncogenic signaling to circRNA regulation. It was also found that circPTPN22 isoforms modulate responses to chemotherapy by regulating the arginine methyltransferase CARM1, a key enzyme involved in transcriptional regulation. Loss of CARM1 expression promoted drug tolerance in chemosensitive ALK(+) lymphoma cells. These findings identify the circPTPN22/CARM1 axis as a regulator of chemosensitivity and propose CARM1 inhibition as a potential strategy to overcome chemoresistance in patients with ALK(+) ALCL.
2026-05-12 | A novel triazole-dithiocarbamate hybrid synergistically enhances cytarabine efficacy and selectivity in anaplastic large cell lymphoma.
The therapeutic efficacy of cytarabine (Ara-C) in anaplastic large cell lymphoma (ALCL) is frequently compromised by dose-limiting myelosuppression and drug resistance. To address this, we developed a series of novel 1,2,3-triazole-dithiocarbamate hybrids designed to target Aurora A kinase and enhance chemosensitivity to Ara-C. Compound 22h emerged as the lead candidate, exhibiting potent Aurora A inhibition (IC₅₀ = 0.296 μM) with threefold preferential inhibition over Aurora B (IC₅₀ = 0.887 μM) and sub-micromolar activity against ALK (IC₅₀ = 0.332 μM). Molecular docking and 100-ns molecular dynamics simulations suggest that 22h engages a putative allosteric pocket in Aurora A, centered on Cys290 (S-score -13.67 kcal/mol), conferring superior stability over ATP-site binding, while simultaneously forming stable interactions within the ALK hinge region. In ALK+ ALCL SR cells, 22h demonstrated significant cytotoxicity (IC₅₀ = 5.10 μM) and high tumor selectivity (SI = 7.0) relative to normal peripheral blood mononuclear cells. Mechanistically, 22h induced potent G₂/M arrest (3.2-fold increase), supporting Aurora A as the primary functional target, alongside cellular ALK depletion as a complementary mechanism. Furthermore, it triggered mitochondrial apoptosis (17.8% total apoptotic fraction) and dismantled chemoresistance pathways by elevating intracellular ROS (3.5-fold) and inhibiting ALDH1 activity (IC₅₀ = 2.8 μg/mL). Crucially, co-treatment with 22h synergistically potentiated Ara-C efficacy (Combination Index = 0.78), reducing the Ara-C IC₅₀ by 12.8-fold (from 27.65 μM to 2.15 μM) and dramatically widening the therapeutic window by 14-fold (SI = 29.6). These findings identify 22h as a novel multi-target scaffold with potent Aurora A/ALK inhibitory activity that restores Ara-C sensitivity in ALCL, supporting its further development as a precision chemosensitizer.
oligonucleotides
2024-12-13 | MicroRNAs and long non-coding RNAs In T-cell lymphoma: Mechanisms, pathway, therapeutic opportunities.
T-cell lymphomas represent non-Hodgkin lymphomas distinguished by the uncontrolled proliferation of malignant T lymphocytes. Classifying these neoplasms and the ongoing investigation of their underlying biological mechanisms remains challenging. Significant subtypes encompass peripheral T-cell lymphomas, anaplastic large-cell lymphomas, cutaneous T-cell lymphomas, and adult T-cell leukemia/lymphoma. A systematic literature survey used electronic databases, including PubMed, Springer Link, Google Scholar, and Web of Science. Search keywords included "T-cell lymphoma," "therapeutic approaches," "RNA therapeutics," "microRNA," and "signaling pathways". T-cell lymphomas are believed to arise from a complex interplay of genetic predispositions and environmental factors. Epstein-Barr virus (EBV) and Human T-cell leukemia virus-1 (HTLV-1), have been implicated as potential etiologic agents. While the exact molecular mechanisms are under investigation, T-cell lymphomas are distinguished by aberrant proliferation of T-cells resulting from dysregulated gene expression. Contemporary research has emphasized the significance of non-coding RNAs, including microRNAs and long non-coding RNAs, in the etiology and advancement of T-cell lymphomas. Certain miRNAs function as tumor suppressors (e.g., miR-451, miR-31, miR-150, miR-29a), while others can act as oncogenes (e.g., miR-223, miR-17-92, miR-155). Additionally, lcRNAs are responsible for modulating gene expression, and their influence on T-cell function suggests their potential outcome as therapeutic targets. Current therapeutic strategies for T-cell lymphomas predominantly rely on chemotherapy, with emerging modalities encompassing immunotherapy and targeted therapies. Despite these advancements, a substantial subset of T-cell lymphomas remains challenging to manage, especially those in advanced stages or refractory to conventional treatments. RNA-based therapeutics represent a promising strategy, offering many advantages such as targeted therapy, potential for personalized medicine, reduced side effects, rapid development, and synergy with other therapies while facing challenges in delivery, immune response, and specificity. Future research should focus on improving delivery systems, modulating immune responses, and optimizing production to unlock its full potential. This review comprehensively explored T-cell lymphomas, delving into their classification, pathogenesis, and existing therapeutic options. Additionally, we explore the evolving function of non-coding RNAs in the pathogenesis of T-cell lymphoma. Furthermore, we discuss the potential of RNA-based therapeutics as a promising treatment strategy.
2023-12-04 | Long non-coding RNA mitophagy and ALK-negative anaplastic lymphoma-associated transcript: a novel regulator of mitophagy in T-cell lymphoma.
Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.
2022-12-30 | Silicone Breast Implant Surface Texture Impacts Gene Expression in Periprosthetic Fibrous Capsules.
Silicone breast implants with smooth outer shells are associated with higher rates of capsular contracture, whereas textured implants have been linked to the development of breast implant-associated anaplastic large cell lymphoma. By assessing the gene expression profile of fibrous capsules formed in response to smooth and textured implants, insight into the development of breast implant-associated abnormalities can be gained. Miniature smooth or textured silicone implants were surgically inserted into female rats ( n = 10) and harvested for the surrounding capsules at postoperative week 6. RNA sequencing and quantitative polymerase chain reaction were performed to identify genes differentially expressed between smooth and textured capsules. For clinical correlation, the expression of candidate genes was assayed in implant capsules harvested from human patients with and without capsular contracture. Of 18,555 differentially expressed transcripts identified, three candidate genes were selected: matrix metalloproteinase-3 ( MMP3 ), troponin-T3 ( TNNT3 ), and neuregulin-1 ( NRG1 ). In textured capsules, relative gene expression and immunostaining of MMP3 and TNNT3 was up-regulated, whereas NRG1 was down-regulated compared to smooth capsules [mean relative fold change, 8.79 ( P = 0.0059), 4.81 ( P = 0.0056), and 0.40 ( P < 0.0001), respectively]. Immunostaining of human specimens with capsular contracture revealed similar gene expression patterns to those of animal-derived smooth capsules. An expression pattern of low MMP3 /low TNNT3 /high NRG1 is specifically associated with smooth implant capsules and human implant capsules with capsular contracture. The authors' clinically relevant breast implant rat model provides a strong foundation to further explore the molecular genetics of implant texture and its effect on breast implant-associated abnormalities. The authors have demonstrated that there are distinct gene expression profiles in response to smooth versus textured breast implants. Since surface texture may be linked to implant-related pathology, further molecular analysis of periprosthetic capsules may yield strategies to mitigate implant-related complications.
2022-07-13 | MiR-181b Inhibits the Proliferation of Lymphoma Rajixi Cell Line by Regulating the Expression of Target Gene FAMLF.
ALCL is an aggressive lymphoma. In most cases, it is diagnosed as stage II or IV in the initial diagnosis, but it has a good response to concurrent chemotherapy with epinephrine. The six-year survival rate is about 50%. This study focused on miR-181b inhibiting the proliferation of the lymphoma Rajixi cell line by regulating the expression of the target gene FAMLF. Observe the morphology of HE with an optical microscope. Immunohistochemical staining was performed on a series of lymphocyte surface markers and cytotoxic granular membranes. In 28ALCL cases, PCR detection of immunoglobulin and T cell receptor gene recombination was performed. Summarize the characteristics of ALCL clinical pathology and the main points of diagnosis and differential diagnosis in daily business, summarize the characteristics of ALK-positive and the cytotoxicity of ALCL, and conduct a preliminary investigation on the cell source, pathological organization and tumor classification. Only four ENBAI subtypes, v-Val, P-THR, V-leu, and P-ALA were detected in lymphoma tissue, and no V-Pro subtype was found. Of the 110 positive lymphomas, 107 were single-digit Rajixi 18 (33%), and the remaining 1 (14%) were double-infected Rajixi. The results show that miR-181b can inhibit the proliferation of the lymphoma Rajixi cell line by regulating the expression of the target gene FAMLF.
2021-11-17 | EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53.
The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found in anaplastic large-cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM-ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM-ALK interacted with Epstein-Barr virus nuclear antigen 1-binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM-ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0 /G1 -phase cell cycle arrest in Ba/F3 cells transformed by NPM-ALK and ALCL patient-derived Ki-JK cells, but not ALCL patient-derived SUDH-L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM-ALK and Ki-JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC-0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt-mTORC1 pathway in NPM-ALK-positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
other
2025-07-13 | Modeling the t(2;5) Translocation of Anaplastic Large Cell Lymphoma Using CRISPR-Mediated Chromosomal Engineering.
ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement, leading to the expression of the NPM-ALK fusion oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the NPM-ALK fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated ALK fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins.
2025-04-24 | Modeling the t(2; 5) Translocation of Anaplastic Large Cell Lymphoma Using CRISPR-Mediated Chromosomal Engineering
ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement leading to the expression of the NPM-ALK fusion-oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in-vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the Npm-Alk fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated Alk fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins.
2024-01-16 | The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a fusion protein generated by a chromosomal translocation, is a causative gene product of anaplastic large cell lymphoma (ALCL). It induces cell proliferation and tumorigenesis by activating the transcription factor, signal transducer and activator of transcription factor 3 (STAT3). We herein demonstrated that STAT3 underwent acetylation at K685 in a manner that was dependent on the kinase activity of NPM-ALK. To investigate the role of STAT3 acetylation in NPM-ALK-induced oncogenesis, we generated Ba/F3 cells expressing NPM-ALK in which STAT3 was silenced by shRNA, named STAT3-KD cells, and then reconstituted wild-type STAT3 or the STAT3 K685R mutant into these cells. The phosphorylation level of the K685R mutant at Y705 and S727 was significantly higher than that of wild-type STAT3 in STAT3-KD cells. The expression of STAT3 target genes, such as IL-6, Pim1, Pim2, and Socs3, was more strongly induced by the reconstitution of the K685R mutant than wild-type STAT3. In addition, the proliferative ability of STAT3-KD cells reconstituted with the K685R mutant was slightly higher than that of STAT3-KD cells reconstituted with wild-type STAT3. In comparisons with the inoculation of STAT3-KD cells reconstituted with wild-type STAT3, the inoculation of STAT3-KD cells reconstituted with the K685R mutant significantly enhanced tumorigenesis and hepatosplenomegaly in nude mice. Collectively, these results revealed for the first time that the acetylation of STAT3 at K685 attenuated NPM-ALK-induced oncogenesis.
2022-09-12 | The nature inspired peptide [T20K]-kalata B1 induces anti-tumor effects in anaplastic large cell lymphoma.
Ribosomally synthesized and post-translationally modified peptides, such as plant cyclotides, are a diverse group of natural products well known as templates in drug discovery and therapeutic lead development. The cyclotide kalata B1 (kB1) has previously been discovered as immunosuppressive agent on T-lymphocytes, and a synthetic version of this peptide, [T20K]kB1 (T20K), has been effective in reducing clinical symptoms, such as inflammation and demyelination, in a mouse model of multiple sclerosis. Based on its T-cell modulatory impact we studied the effects of T20K and several analogs on the proliferation of anaplastic large cell lymphoma (ALCL), a heterogeneous group of clinically aggressive diseases associated with poor prognosis. T20K, as a prototype drug candidate, induces apoptosis and a proliferation arrest in human lymphoma T-cell lines (SR786, Mac-2a and the Jurkat E6.1) in a concentration dependent fashion, at least partially via increased STAT5 and p53 signaling. In contrary to its effect on IL-2 signaling in lymphocytes, the cytokine levels are not altered in lymphoma cells. In vivo mouse experiments revealed a promising activity of T20K on these cancer cells including decreased tumor weight and increased apoptosis. This study opens novel avenues for developing cyclotide-based drug candidates for therapy of patients with ALCL.
2019-02-26 | Targeting ALK in Cancer: Therapeutic Potential of Proapoptotic Peptides
ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.
cell therapies
2026-05-14 | Chimeric Antigen Receptor T‑Cell Therapy Targeting Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30) for Relapsed or Refractory Anaplastic Large Cell Lymphoma: Rationale, Strategies, and Emerging Clinical Evidence.
Chimeric Antigen Receptor (CAR) T-cell therapy has fundamentally altered the treatment paradigm for relapsed or refractory (R/R) B-cell malignancies. However, translating this success to T-cell lymphomas has been impeded by a critical biological barrier: fratricide. This process describes the self-destruction of therapeutic T-cells caused by their shared expression of target antigens, such as Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30), following activation. Anaplastic Large Cell Lymphoma (ALCL), characterized by its uniform and high-level expression of CD30, represents both an ideal candidate for this approach and a significant scientific challenge. This comprehensive review begins by outlining the established landscape of approved CD19- and BCMA-directed CAR-T therapies to provide context. It then focuses specifically on the application of anti-CD30 CAR-T therapy for ALCL, examining the molecular mechanisms that drive fratricide. We explore the innovative engineering and manufacturing strategies developed to overcome this obstacle, including ultrarapid production protocols, the selection of virus-specific T-cells, and precise genetic disruption of the TNFRSF8 gene using CRISPR/Cas9 technology. An analysis of early phase clinical trial data reveals encouraging efficacy, with high rates of durable complete responses observed even in heavily pretreated patients who have failed brentuximab vedotin therapy. Furthermore, these initial studies report a remarkably favorable safety profile, characterized by a near absence of severe cytokine release syndrome and neurotoxicitya feature that distinctly contrasts with CD19-directed therapies. While these findings are promising, it is essential to acknowledge that the current evidence base remains preliminary, derived from small, heterogeneous patient cohorts and requiring validation in larger, more definitive trials with extended follow-up. By successfully addressing the challenge of fratricide, anti-CD30 CAR-T therapy holds the potential to become a transformative and potentially curative option for patients with R/R ALCL and may offer a valuable blueprint for developing effective immunotherapies against other T-cell malignancies.
2026-05-08 | Autologous and allogeneic hematopoietic cell transplantation in children and adults with high-risk anaplastic large cell lymphoma.
Both autologous and allogeneic hematopoietic cell transplantation (HCT) have been used to treat high-risk anaplastic large cell lymphoma (ALCL) that has failed conventional chemotherapy. However, many patients are not able to fully eradicate disease prior to HCT, making the role of either form of HCT unclear. The aim of this study was to collect characteristics and outcomes of patients who underwent either autologous and/or allogeneic HCT and determine the role that disease status at HCT plays in overall survival (OS). To address this, we collected data on 41 patients with ALCL that underwent autologous (n=24) and/or allogeneic (n=17) HCT at our center between 1997-2020. The 5-year estimated progression-free survival (PFS) and OS for the autologous HCT group was 40% (95% confidence interval, 20-59%) and 53% (31-71%), while for the allogeneic HCT group it was 65% (38-92%) and 65% (38-82%), respectively. For transplants performed in 2009 or later, 5-year OS was 91% (51-99%) in the allogeneic HCT group, and 51% (23-73%) in the autologous HCT group. Notable was that for those who entered transplant with detectable disease, 5-year OS was 50% (15-77%) with allogeneic HCT whereas it was 27% (7-54%) for autologous HCT. These data confirm that HCT is a potentially curative therapy, and allogeneic HCT may have a survival advantage over autologous HCT when there is detectable disease prior to HCT.
2026-04-03 | Abstract 5615: ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma
Abstract Introduction: Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL) is a rare subtype of T-cell lymphoma driven by nucleophosmin 1 (NPM1)-ALK fusion protein. Treatment with standard chemotherapy or ALK tyrosine kinase inhibitor crizotinib is highly effective; however, a significant portion of patients still experience relapses or refractory disease, highlighting the need for innovative therapeutic options. Our group has recently identified two ALK-specific T cell receptors targeting the human ALK peptide RPRPSQPSSL presented by HLA-B*07:02 (B7) and demonstrated specific and robust anti-tumor activity of ALK.TCR-T cells (ALK.TCR-T) in ALK+ non-small cell lung cancer [Mecca et al, Cancer res, 2024]. In this work, we aimed to address the efficacy of ALK.TCR-T in multiple models of ALK+ ALCL. Methods: Two ALK-specific TCRs were retrovirally transduced into human CD3+ T cells to generate ALK.TCR-T1 and ALK.TCR-T2. The anti-tumor activity of ALK.TCR-T was tested both in vitro and in vivo against a panel of crizotinib-sensitive and crizotinib-resistant ALK+ ALCL models. The specificity of peptide-MHC recognition was evaluated by employing ALK+/B7+, ALK+/B7-, and ALK-/B7+ cells. For in vivo studies, NSG mice were injected intravenously with ALK+ ALCL cell lines, and, after engraftment, treated with ALK.TCR-T, alone or in combination with crizotinib. Mice received 50mg/kg crizotinib by oral gavage for 10 days. Tumor growth was evaluated weekly by bioluminescence imaging. Results: In vitro killing assays demonstrated that both ALK.TCR-T selectively recognize and eliminate 80-100% of ALK+/B7+ ALCL, while no killing occurred in ALK+/B7- or ALK-/B7+ models, confirming that ALK.TCR-T specifically target the ALK peptide RPRPSQPSSL presented by HLA-B*07:02. Moreover, ALK-TCR-T were equally effective in killing crizotinib-resistant ALCL cells, independently of the mechanism driving the resistance to crizotinib. Interestingly, the combination of ALK.TCR-T and crizotinib potentiated the killing of crizotinib-sensitive ALK+ ALCL even at unfavorable E:T ratios (1:5 and 1:10).A single treatment with ALK.TCR-T significantly slowed tumor growth in an ALK+/B7+ systemic tumor model and increased the survival of mice, compared to treatment with irrelevant TCR-T cells. The combined treatment with ALK.TCR-T and crizotinib resulted in a further enhancement of tumor regression and mouse survival, with 50% (5/10) mice with no evidence of tumor 40 days after ALK.TCR-T injection. Conclusions: We demonstrated that ALK.TCR-T show specific and potent anti-tumor activity against multiple ALK+ ALCL models both in vitro and in vivo. The combination of ALK.TCR-T and crizotinib further potentiate the ability of ALK.TCR-T to control tumor growth and extend the survival of mice. These results lay the basis for developing a novel immunotherapy strategy for patients with ALK+ ALCL. Citation Format: Simone Piane, Carmen Mecca, Nirmala Tilija Pun, Ana Azambuja, Luca Alessandri, Phuc Bao Nguyen, Elisa Bergaggio, Gabriele Saccu, Alessandro Gasparetto, Haley Ohlson, Claudia Voena, Marcos Simoes-Costa, Roberto Chiarle. ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5615.
2026-01-21 | Positionally Stable Smooth Implants: An In Vivo Submuscular Model.
Following the voluntary recall of certain textured implants due to recognized association with BIA-ALCL, plastic surgeons lost the major benefit of textured surfaces-positional stability. We have engineered a novel smooth-surface breast implant design featuring small millimeter-dimension cylindrical surface wells that promote tissue ingrowth and stabilize the implant. These Positionally Stable Smooth Implants (PSSI) previously demonstrated superior positional stability versus smooth implants (and comparable to textured) in a subcutaneous in vivo model. Here, we investigate PSSI in a submuscular model. Hemispherical miniature breast implants were fabricated with polydimethylsiloxane. PSSI implants featured wells 2mm wide by 1mm deep with 26, 52, or 70 wells/implant. Miniature smooth and textured implants served as controls. Six implants per group were placed under bilateral latissimus dorsi muscles of female Sprague-Dawley rats. Implant position was evaluated at 2, 4, 8, and 12 weeks, then explanted. Over 12 weeks, PSSI exhibited significantly less rotation than smooth implants (p<0.001) and comparable to that of textured implants. Textured and some PSSI capsules had significantly lower collagen density and smooth muscle actin expression compared to smooth implants (p<0.05). PSSI and smooth capsules had lower pro-inflammatory M1 macrophage expression and a lower M1/M2 macrophage ratio than textured capsules (p<0.01). PSSI implants demonstrated significantly increased rotational stability and reduced collagen density and myofibroblast presence compared to smooth implants, as well as significantly decreased expression of pro-inflammatory macrophages compared to textured implants. These data suggest a promising alternative to texturing for providing positional stability of implants in the submuscular plane.
2025-11-29 | Emerging therapeutic strategies for CD30-positive lymphomas.
The antibody-drug conjugate brentuximab vedotin (BV) has significantly improved outcomes for CD30-expressing lymphomas. The ECHELON-2 trial established BV combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as a frontline standard for systemic anaplastic large cell lymphoma, demonstrating superior survival over the traditional CHOP regimen. Despite this progress, the limitations of a universal BV + CHP standard are increasingly apparent, and the therapeutic landscape is rapidly diversifying. This review critically evaluates the evidence supporting BV + CHP, including methodological considerations of the ECHELON-2 trial, and explores the expanding arsenal of novel therapies. We assess alternative strategies, such as BV-based combinations with immunotherapies or alternative chemotherapies, the integration of other targeted agents, and the transformative potential of advanced cellular treatments like anti-CD30 chimeric antigen receptor (CAR)-T cell therapy for relapsed/refractory disease. The collective evidence signals a paradigm shift from a one-size-fits-all approach toward personalized, precision-driven strategies aimed at maximizing efficacy, minimizing toxicity, and improving long-term quality of life for patients with CD30-positive lymphomas.
antibodies
2026-08-15 | ALK-negative anaplastic large cell lymphoma in pediatric and adolescent patients: a mini-review.
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.
2026-08-01 | Intravenous pharmacologic ascorbate as a redox modulator and chemosensitizer in targeted Cancer therapies.
Intravenous pharmacologic ascorbate represents a re-emerging oncologic adjunct that exploits concentration-dependent pro-oxidant effects to selectively induce oxidative stress in malignant cells while preserving normal tissue. Supported by recent clinical data in metastatic pancreatic ductal adenocarcinoma, where high-dose ascorbate combined with gemcitabine and nab-paclitaxel has improved survival outcomes, this review proposes a broader therapeutic paradigm. This paper presents a hypothesis-driven translational perspective that synthesises current mechanistic evidence with a novel therapeutic proposal. Using Brentuximab Vedotin-based therapy for CD30-positive lymphomas as a representative model, we delineate the multi-mechanistic potential of intravenous pharmacologic ascorbate to enhance targeted treatment regimens. Intravenous pharmacologic ascorbate may act as both a redox disruptor and chemosensitizer-amplifying antibody-drug conjugate cytotoxicity through oxidative stress potentiation, apoptotic enhancement, and tumour microenvironment modulation. While preclinical evidence from related chemotherapy contexts suggests potential for synergistic interactions, direct evidence for this specific combination is currently lacking, and the mechanisms discussed remain hypothetical until validated in appropriate models. Notably, the redox-modulating properties of intravenous pharmacologic ascorbate could theoretically address common resistance pathways in cancer, such as the upregulation of endogenous antioxidant defences. Furthermore, emerging data suggests intravenous pharmacologic ascorbate may also influence epigenetic regulation in cancer cells through modulation of α-ketoglutarate-dependent dioxygenases, including ten-eleven translocation enzymes and histone demethylases, potentially reversing hypermethylation-associated silencing of tumour suppressor genes. This paper advocates for preclinical validation followed by well-designed phase II clinical trials to evaluate the safety, efficacy, and pharmacodynamics of intravenous pharmacologic ascorbate combined with targeted therapies. If the hypothesised benefits are confirmed, this approach could position intravenous pharmacologic ascorbate as an accessible, low-toxicity adjunct capable of improving long-term outcomes and quality of life for patients with aggressive malignancies.
2026-07-31 | Breast implant associated anaplastic large cell lymphoma is a heterogeneous T cell disease with active pro-tumour cross-talk and immune suppression.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T cell lymphoma in women with textured implants. Little is known about the cell of origin (COO) and whether the tumour immune microenvironment (TIME) is critical for BIA-ALCL survival. Single-cell RNA sequencing revealed BIA-ALCL cells were heterogeneous with unique gene profiles per patient and signature genes BATF3, SERPINS, TNFSFR8, and IL2RA. The COO is a CD4+ or CD8+ memory T cell identified through rearranged TCR and gene expression. The BIA-ALCL TIME included distinct myeloid clusters, dendritic cells (DCs), and monocytes, which may support lymphoma cells. Cytokines IL-13, IL-10, TNF and secretory PDL1 were increased in BIA-ALCL seroma, indicating an immunosuppressive TIME. Interactome analysis revealed a complex network among lymphoma cells, dominated by IL-13, IL-10, and TNF members. Endogenous CD8+ T cells exhibit higher checkpoint expression than benign seromas. No clonal relationship exists between BIA-ALCL and endogenous T cells. Tissue-archetype and gene-expression analysis revealed T-cell exclusion and immunosuppressive TIME in invasive disease. In summary, BIA-ALCL cells are diverse with markedly different TIME across stages. The TIME provides immunosuppressive signals to activated/exhausted T cells and homeostatic signals that promote BIA-ALCL proliferation. These new findings may offer novel therapeutic targets for advanced disease patients.
2026-07-28 | CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma.
Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell lymphomas (T-NHLs) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. While case reports and individual Anaplastic Large Cell Lymphoma (ALCL) cases enrolled in T-NHL trials demonstrated favourable responses to ICI, hyperprogression was observed in other T-NHL subtypes. We therefore utilized a syngeneic mouse model of ALK+ ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and NK cells. Innate and adaptive immune cell infiltration was confirmed on a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in approximately 50% of treated animals. Mechanistically, PD-L1 blockade reversed Treg-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby prolonging survival significantly. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced anti-tumour responses in murine ALCL. CD4+ T cells of non-responder animals exhibited an exhausted phenotype and a transcriptomic Th22-like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune-evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.
2026-07-23 | ALK-Negative Systemic Anaplastic Large Cell Lymphoma with Cutaneous Involvement Initially Mimicking Primary Cutaneous Disease: A Case Report.
Anaplastic large cell lymphoma (ALCL), a subgroup of T-cell non-Hodgkin's lymphoma, is a relatively uncommon malignancy with a highly variable prognosis. Systemic ALK-negative status and high Ki-67 expression are generally associated with poor outcomes in ALCL patients. Systemic ALK-negative ALCL presenting initially with cutaneous involvement is rare, with only a few cases reported in the literature. The aggressive clinical course of systemic ALK-negative ALCL with cutaneous lesions contrasts sharply with the indolent behavior of primary cutaneous ALCL (C-ALCL). Accurate distinction requires integration of histopathological and immunophenotypic findings. In particular, negativity for cutaneous lymphocyte antigen (CLA) is a useful discriminator, as primary C-ALCL typically expresses CLA while systemic cases often do not. Accumulating more clinical data is essential to better characterize this entity and guide therapeutic decisions. Here, we report a case of aggressive ALK-negative systemic ALCL that presented with cutaneous nodules as the initial manifestation, clinically mimicking primary C-ALCL.
small molecules
2026-07-31 | Arsenic trioxide promotes a glue‑like interaction to drive STUB1-mediated NPM-ALK degradation in ALK+ ALCL.
The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion constitutively activates ALK tyrosine kinase, driving oncogenesis in anaplastic large cell lymphoma (ALCL). While arsenic trioxide (ATO) exhibits therapeutic potential, its precise mechanism remains elusive, limiting clinical application. Here, we used a combined approach of E3 ligase library screening, ATO chemical proteomics, and NPM-ALK immunoprecipitation-mass spectrometry to reveal that ATO regulates NPM-ALK stability via the E3 ligase STUB1. Clinically, high STUB1 expression correlates with improved survival, identifying it as a candidate favorable prognostic biomarker in NPM-ALK+ ALCL. Mechanistically, ATO promotes a glue‑like interaction that stabilizes the ternary complex of STUB1 and NPM-ALK, promoting ubiquitination at K174 and subsequent proteasomal degradation. Furthermore, structural modeling, domain mapping, and point mutations support a proposed arsenic-dependent interaction model involving STUB1 Cys83, Cys103, and NPM-ALK Cys599, which may modulate the STUB1-NPM-ALK interface and enhance their interaction, thereby promoting ubiquitin-mediated degradation. Crucially, we demonstrate that STUB1 overexpression or pharmacological activation using the FDA-approved cardiac glycoside Deslanoside synergizes profoundly with ATO to inhibit tumor growth both in vitro and in vivo. These findings provide novel mechanistic insight into ATO's action in NPM-ALK+ ALCL and reveal new therapeutic strategies and candidate prognostic biomarkers for patient management.
2026-07-01 | Endobronchial anaplastic large cell lymphoma presenting as unilateral white-out lung: Successful chemotherapy in an adolescent: A case report
Abstract White-out lung encountered in the pediatric emergency room can lead to life-threatening respiratory failure. A 16-year-old boy presented with “white-out” lung on his chest X-ray. He needed mechanical ventilation for respiratory failure. Bronchoscopy revealed that his left main bronchus was completely blocked by a vascular mass. A biopsy confirmed anaplastic large-cell lymphoma (ALCL). After starting chemotherapy, he showed dramatic improvement within 5 days, was successfully extubated, and transitioned to care under the pediatric hematology–oncology team. This case report highlights endobronchial ALCL, a rare cause of “white-out lung,” diagnosed via prompt bronchoscopy and favorable outcome with a short course of chemotherapy.
2026-06-25 | [A patient with dizziness and gait instability - a diagnostic challenge].
A 58-year-old patient presented with progressive cerebellar ataxia and lymphocytic pleocytosis with normal MRI findings. Detection of Anti-TR(DNER) antibodies led to the diagnosis of paraneoplastic encephalitis. Tumor workup revealed anaplastic large cell lymphoma. Combined immunotherapy and chemotherapy resulted in clinical stabilization.
2026-06-05 | CircRNAs derived from the tyrosine phosphatase PTPN22 impact chemosensitivity in ALK-positive T-cell lymphomas.
Anaplastic large cell lymphoma (ALCL) is a subtype of T-cell non-Hodgkin lymphoma (NHL), classified into ALK(+) and ALK(-) subtypes, based on translocations of the ALK gene. ALK(+) ALCL have a favorable prognosis with polychemotherapy, yet some patients develop early chemoresistance, leading to treatment failure. The molecular mechanisms underlying this resistance remain poorly defined. Circular RNAs (circRNAs) have recently emerged as regulators of drug resistance in cancer, but their role in T-NHLs is largely unexplored. A comprehensive analysis of circRNA expression was performed here in primary ALK(+) ALCL biopsies. RNA-Seq identified 12 circRNAs associated with early relapse, including isoforms from the PTPN22 gene (circPTPN22), significantly upregulated in relapsed patients. Functional analyses showed that the ALK/STAT3 signaling pathway regulates circPTPN22 expression, linking oncogenic signaling to circRNA regulation. It was also found that circPTPN22 isoforms modulate responses to chemotherapy by regulating the arginine methyltransferase CARM1, a key enzyme involved in transcriptional regulation. Loss of CARM1 expression promoted drug tolerance in chemosensitive ALK(+) lymphoma cells. These findings identify the circPTPN22/CARM1 axis as a regulator of chemosensitivity and propose CARM1 inhibition as a potential strategy to overcome chemoresistance in patients with ALK(+) ALCL.
2026-05-12 | A novel triazole-dithiocarbamate hybrid synergistically enhances cytarabine efficacy and selectivity in anaplastic large cell lymphoma.
The therapeutic efficacy of cytarabine (Ara-C) in anaplastic large cell lymphoma (ALCL) is frequently compromised by dose-limiting myelosuppression and drug resistance. To address this, we developed a series of novel 1,2,3-triazole-dithiocarbamate hybrids designed to target Aurora A kinase and enhance chemosensitivity to Ara-C. Compound 22h emerged as the lead candidate, exhibiting potent Aurora A inhibition (IC₅₀ = 0.296 μM) with threefold preferential inhibition over Aurora B (IC₅₀ = 0.887 μM) and sub-micromolar activity against ALK (IC₅₀ = 0.332 μM). Molecular docking and 100-ns molecular dynamics simulations suggest that 22h engages a putative allosteric pocket in Aurora A, centered on Cys290 (S-score -13.67 kcal/mol), conferring superior stability over ATP-site binding, while simultaneously forming stable interactions within the ALK hinge region. In ALK+ ALCL SR cells, 22h demonstrated significant cytotoxicity (IC₅₀ = 5.10 μM) and high tumor selectivity (SI = 7.0) relative to normal peripheral blood mononuclear cells. Mechanistically, 22h induced potent G₂/M arrest (3.2-fold increase), supporting Aurora A as the primary functional target, alongside cellular ALK depletion as a complementary mechanism. Furthermore, it triggered mitochondrial apoptosis (17.8% total apoptotic fraction) and dismantled chemoresistance pathways by elevating intracellular ROS (3.5-fold) and inhibiting ALDH1 activity (IC₅₀ = 2.8 μg/mL). Crucially, co-treatment with 22h synergistically potentiated Ara-C efficacy (Combination Index = 0.78), reducing the Ara-C IC₅₀ by 12.8-fold (from 27.65 μM to 2.15 μM) and dramatically widening the therapeutic window by 14-fold (SI = 29.6). These findings identify 22h as a novel multi-target scaffold with potent Aurora A/ALK inhibitory activity that restores Ara-C sensitivity in ALCL, supporting its further development as a precision chemosensitizer.
oligonucleotides
2024-12-13 | MicroRNAs and long non-coding RNAs In T-cell lymphoma: Mechanisms, pathway, therapeutic opportunities.
T-cell lymphomas represent non-Hodgkin lymphomas distinguished by the uncontrolled proliferation of malignant T lymphocytes. Classifying these neoplasms and the ongoing investigation of their underlying biological mechanisms remains challenging. Significant subtypes encompass peripheral T-cell lymphomas, anaplastic large-cell lymphomas, cutaneous T-cell lymphomas, and adult T-cell leukemia/lymphoma. A systematic literature survey used electronic databases, including PubMed, Springer Link, Google Scholar, and Web of Science. Search keywords included "T-cell lymphoma," "therapeutic approaches," "RNA therapeutics," "microRNA," and "signaling pathways". T-cell lymphomas are believed to arise from a complex interplay of genetic predispositions and environmental factors. Epstein-Barr virus (EBV) and Human T-cell leukemia virus-1 (HTLV-1), have been implicated as potential etiologic agents. While the exact molecular mechanisms are under investigation, T-cell lymphomas are distinguished by aberrant proliferation of T-cells resulting from dysregulated gene expression. Contemporary research has emphasized the significance of non-coding RNAs, including microRNAs and long non-coding RNAs, in the etiology and advancement of T-cell lymphomas. Certain miRNAs function as tumor suppressors (e.g., miR-451, miR-31, miR-150, miR-29a), while others can act as oncogenes (e.g., miR-223, miR-17-92, miR-155). Additionally, lcRNAs are responsible for modulating gene expression, and their influence on T-cell function suggests their potential outcome as therapeutic targets. Current therapeutic strategies for T-cell lymphomas predominantly rely on chemotherapy, with emerging modalities encompassing immunotherapy and targeted therapies. Despite these advancements, a substantial subset of T-cell lymphomas remains challenging to manage, especially those in advanced stages or refractory to conventional treatments. RNA-based therapeutics represent a promising strategy, offering many advantages such as targeted therapy, potential for personalized medicine, reduced side effects, rapid development, and synergy with other therapies while facing challenges in delivery, immune response, and specificity. Future research should focus on improving delivery systems, modulating immune responses, and optimizing production to unlock its full potential. This review comprehensively explored T-cell lymphomas, delving into their classification, pathogenesis, and existing therapeutic options. Additionally, we explore the evolving function of non-coding RNAs in the pathogenesis of T-cell lymphoma. Furthermore, we discuss the potential of RNA-based therapeutics as a promising treatment strategy.
2023-12-04 | Long non-coding RNA mitophagy and ALK-negative anaplastic lymphoma-associated transcript: a novel regulator of mitophagy in T-cell lymphoma.
Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.
2022-12-30 | Silicone Breast Implant Surface Texture Impacts Gene Expression in Periprosthetic Fibrous Capsules.
Silicone breast implants with smooth outer shells are associated with higher rates of capsular contracture, whereas textured implants have been linked to the development of breast implant-associated anaplastic large cell lymphoma. By assessing the gene expression profile of fibrous capsules formed in response to smooth and textured implants, insight into the development of breast implant-associated abnormalities can be gained. Miniature smooth or textured silicone implants were surgically inserted into female rats ( n = 10) and harvested for the surrounding capsules at postoperative week 6. RNA sequencing and quantitative polymerase chain reaction were performed to identify genes differentially expressed between smooth and textured capsules. For clinical correlation, the expression of candidate genes was assayed in implant capsules harvested from human patients with and without capsular contracture. Of 18,555 differentially expressed transcripts identified, three candidate genes were selected: matrix metalloproteinase-3 ( MMP3 ), troponin-T3 ( TNNT3 ), and neuregulin-1 ( NRG1 ). In textured capsules, relative gene expression and immunostaining of MMP3 and TNNT3 was up-regulated, whereas NRG1 was down-regulated compared to smooth capsules [mean relative fold change, 8.79 ( P = 0.0059), 4.81 ( P = 0.0056), and 0.40 ( P < 0.0001), respectively]. Immunostaining of human specimens with capsular contracture revealed similar gene expression patterns to those of animal-derived smooth capsules. An expression pattern of low MMP3 /low TNNT3 /high NRG1 is specifically associated with smooth implant capsules and human implant capsules with capsular contracture. The authors' clinically relevant breast implant rat model provides a strong foundation to further explore the molecular genetics of implant texture and its effect on breast implant-associated abnormalities. The authors have demonstrated that there are distinct gene expression profiles in response to smooth versus textured breast implants. Since surface texture may be linked to implant-related pathology, further molecular analysis of periprosthetic capsules may yield strategies to mitigate implant-related complications.
2022-07-13 | MiR-181b Inhibits the Proliferation of Lymphoma Rajixi Cell Line by Regulating the Expression of Target Gene FAMLF.
ALCL is an aggressive lymphoma. In most cases, it is diagnosed as stage II or IV in the initial diagnosis, but it has a good response to concurrent chemotherapy with epinephrine. The six-year survival rate is about 50%. This study focused on miR-181b inhibiting the proliferation of the lymphoma Rajixi cell line by regulating the expression of the target gene FAMLF. Observe the morphology of HE with an optical microscope. Immunohistochemical staining was performed on a series of lymphocyte surface markers and cytotoxic granular membranes. In 28ALCL cases, PCR detection of immunoglobulin and T cell receptor gene recombination was performed. Summarize the characteristics of ALCL clinical pathology and the main points of diagnosis and differential diagnosis in daily business, summarize the characteristics of ALK-positive and the cytotoxicity of ALCL, and conduct a preliminary investigation on the cell source, pathological organization and tumor classification. Only four ENBAI subtypes, v-Val, P-THR, V-leu, and P-ALA were detected in lymphoma tissue, and no V-Pro subtype was found. Of the 110 positive lymphomas, 107 were single-digit Rajixi 18 (33%), and the remaining 1 (14%) were double-infected Rajixi. The results show that miR-181b can inhibit the proliferation of the lymphoma Rajixi cell line by regulating the expression of the target gene FAMLF.
2021-11-17 | EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53.
The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found in anaplastic large-cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM-ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM-ALK interacted with Epstein-Barr virus nuclear antigen 1-binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM-ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0 /G1 -phase cell cycle arrest in Ba/F3 cells transformed by NPM-ALK and ALCL patient-derived Ki-JK cells, but not ALCL patient-derived SUDH-L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM-ALK and Ki-JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC-0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt-mTORC1 pathway in NPM-ALK-positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
other
2025-07-13 | Modeling the t(2;5) Translocation of Anaplastic Large Cell Lymphoma Using CRISPR-Mediated Chromosomal Engineering.
ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement, leading to the expression of the NPM-ALK fusion oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the NPM-ALK fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated ALK fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins.
2025-04-24 | Modeling the t(2; 5) Translocation of Anaplastic Large Cell Lymphoma Using CRISPR-Mediated Chromosomal Engineering
ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement leading to the expression of the NPM-ALK fusion-oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in-vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the Npm-Alk fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated Alk fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins.
2024-01-16 | The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a fusion protein generated by a chromosomal translocation, is a causative gene product of anaplastic large cell lymphoma (ALCL). It induces cell proliferation and tumorigenesis by activating the transcription factor, signal transducer and activator of transcription factor 3 (STAT3). We herein demonstrated that STAT3 underwent acetylation at K685 in a manner that was dependent on the kinase activity of NPM-ALK. To investigate the role of STAT3 acetylation in NPM-ALK-induced oncogenesis, we generated Ba/F3 cells expressing NPM-ALK in which STAT3 was silenced by shRNA, named STAT3-KD cells, and then reconstituted wild-type STAT3 or the STAT3 K685R mutant into these cells. The phosphorylation level of the K685R mutant at Y705 and S727 was significantly higher than that of wild-type STAT3 in STAT3-KD cells. The expression of STAT3 target genes, such as IL-6, Pim1, Pim2, and Socs3, was more strongly induced by the reconstitution of the K685R mutant than wild-type STAT3. In addition, the proliferative ability of STAT3-KD cells reconstituted with the K685R mutant was slightly higher than that of STAT3-KD cells reconstituted with wild-type STAT3. In comparisons with the inoculation of STAT3-KD cells reconstituted with wild-type STAT3, the inoculation of STAT3-KD cells reconstituted with the K685R mutant significantly enhanced tumorigenesis and hepatosplenomegaly in nude mice. Collectively, these results revealed for the first time that the acetylation of STAT3 at K685 attenuated NPM-ALK-induced oncogenesis.
2022-09-12 | The nature inspired peptide [T20K]-kalata B1 induces anti-tumor effects in anaplastic large cell lymphoma.
Ribosomally synthesized and post-translationally modified peptides, such as plant cyclotides, are a diverse group of natural products well known as templates in drug discovery and therapeutic lead development. The cyclotide kalata B1 (kB1) has previously been discovered as immunosuppressive agent on T-lymphocytes, and a synthetic version of this peptide, [T20K]kB1 (T20K), has been effective in reducing clinical symptoms, such as inflammation and demyelination, in a mouse model of multiple sclerosis. Based on its T-cell modulatory impact we studied the effects of T20K and several analogs on the proliferation of anaplastic large cell lymphoma (ALCL), a heterogeneous group of clinically aggressive diseases associated with poor prognosis. T20K, as a prototype drug candidate, induces apoptosis and a proliferation arrest in human lymphoma T-cell lines (SR786, Mac-2a and the Jurkat E6.1) in a concentration dependent fashion, at least partially via increased STAT5 and p53 signaling. In contrary to its effect on IL-2 signaling in lymphocytes, the cytokine levels are not altered in lymphoma cells. In vivo mouse experiments revealed a promising activity of T20K on these cancer cells including decreased tumor weight and increased apoptosis. This study opens novel avenues for developing cyclotide-based drug candidates for therapy of patients with ALCL.
2019-02-26 | Targeting ALK in Cancer: Therapeutic Potential of Proapoptotic Peptides
ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.
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Drug Discovery Landscape
8 orphan drug designations for Anaplastic large cell lymphoma, including 2 approved therapies.
8 orphan drug designations for Anaplastic large cell lymphoma, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
CD30-Targeted Genetically-modified Autologous T-cell immunotherapy | cell therapies | FDA | 2024-01-29 | — | Wu Han Bio-raid Biotech Co., Ltd. |
Belinostat | small molecules | EMA | 2012-10-10 | — | Onxeo DK, Filial af Onxeo S.A., Frankrig |
crizotinib [Xalkori] | small molecules | FDA | 2012-09-28 | 2021-01-14 | Pfizer, Inc. |
Mogamulizumab | antibodies | EMA | 2012-01-11 | — | Kyowa Kirin Holdings B.V. |
mogamulizumab | antibodies | FDA | 2010-11-02 | — | Kyowa Kirin Pharmaceutical Development, Inc. |
Darinaparsin | small molecules | FDA | 2010-09-13 | — | Solasia Pharma K.K. |
Brentuximab vedotin [Adcetris] | antibodies | EMA | 2009-01-15 | — | Takeda Pharma A/S |
brentuximab vedotin [Adcetris] | antibodies | FDA | 2008-10-23 | 2011-08-19 | Seagen Inc. |
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