2026-08-13 | Rewiring of the Apoptotic Rheostat in HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of apoptotic pathways, which is a key determinant of long-term viral persistence and favors malignant transformation. This review describes the mechanisms through which HTLV-1 gene products, including Tax and HBZ, reprogram host-cell signaling controlling the "apoptotic rheostat", an integrated network connecting redox metabolism, and response to apoptotic cues and immune pressure. We also highlight emerging therapeutic strategies to restore sensitivity to apoptosis, including BH3-mimetic drugs and rational combination approaches. Deciphering how HTLV-1 reconfigures the apoptotic network provides a conceptual and therapeutic framework for targeting death pathway vulnerabilities in ATLL and potentially other hematological neoplasms.
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2026-08-12 | HTLV-1-associated diseases: a systematic review.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with a broad spectrum of clinical manifestations. While most people living with HTLV-1 remain asymptomatic, a proportion develops severe conditions such as adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis. Increasing evidence also indicates that HTLV-1 infection is related to multiple systemic complications involving different organ systems (including neurological, pulmonary, dermatological, rheumatological, and ophthalmological disorders) and opportunistic infections. Given the growing recognition of these diverse manifestations, this review aims to compile and synthesize the scientific evidence regarding clinical manifestations, co-infections, opportunistic diseases, and complications related to HTLV-1 infection.
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2026-08-02 | The requirement of MALT1 activity for the growth of adult T cell leukemia/lymphoma.
Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy with poor prognosis. Recurrent genetic alterations in T cell receptor (TCR) signaling components, including PLCG1, PRKCB, and CARD11, highlight the biological relevance of this pathway in ATL. We focused on mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), a key regulator of TCR signaling that functions through complex formation with CARD11 and BCL10, and developed a potent and selective MALT1 protease inhibitor, CRD-1441551. CRD-1441551 exhibited variable antitumor effects across ATL models both in vitro and in vivo. Among three ATL cell lines and five patient-derived xenograft models, two demonstrated marked sensitivity, three showed modest responses, and three were unresponsive. Notably, therapeutic responses were more frequently observed in models with constitutive MALT1 activation accompanied by enhanced MALT1-NF-κB signaling. These findings suggest that CRD-1441551 preferentially targets a subset of ATL, in which tumor growth is dependent on the MALT1-driven NF-κB pathway.
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2026-07-30 | Long-term remission of chronic-type adult T-cell leukemia/lymphoma associated with Graves' disease treated with methimazole.
Adult T-cell leukemia/lymphoma (ATL) is a rare T-cell malignancy, where the chronic type often progresses to an acute form in the presence of poor prognostic factors. We report a remarkable case of chronic-type ATL that achieved long-term hematologic and molecular remission following methimazole treatment for concomitant Graves' disease. A 58-year-old woman was diagnosed with chronic-type ATL in 2022. Her disease showed gradual progression with elevated soluble interleukin-2 receptor (sIL-2R) levels and lactate dehydrogenase. In 2023, she developed Sjögren's syndrome and Graves' disease. Following the initiation of methimazole for hyperthyroidism, her abnormal lymphocyte counts and sIL-2R levels unexpectedly and rapidly decreased. She has maintained clinical stability for over two years without any cytotoxic chemotherapy. Multi-color flow cytometry confirmed the disappearance of the CD4+/CADM1+/CD7- ATL cell population in the peripheral blood. Furthermore, longitudinal genomic profiling using Target-seq revealed a significant reduction in the variant allele frequencies of major driver clones, including a PDCD1 frameshift mutation, and a shift from monoclonal expansion to a polyclonal HTLV-1 carrier state. This case provides the first clinical evidence of a potential anti-ATL effect of methimazole and underscores the importance of the endocrine-immune axis in HTLV-1-associated malignancies, warranting further investigation into antithyroid therapy as a novel treatment strategy for indolent ATL.
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2026-07-28 | Investigating the Mechanisms Underlying Cell Death Induction by a Tributyltin Molecule in HTLV-1-Infected Cells Dependent or Not on IL-2 as a Growth Factor.
Human T-Lymphotropic virus type 1 (HTLV-1) lifelong infects at least 5-10 million people worldwide, a minority of whom develop severe lethal diseases including adult T-cell Leukemia/lymphoma and HTLV-1-associated myelopathy or tropical spastic paraparesis. Currently, no vaccines or curative therapies to fight HTLV-1 infection or diseases are available. Recently we found that a tributyltin molecule, Bu3SnOCOCF3 (TBT), which is more potent than cisplatin in inducing cytotoxic effects towards a panel of cell lines including high-tumorigenic cells, also exerted potent cytotoxic effects even towards HTLV-1-infected cell lines, mimicking different states of virus-driven transformation. The type of cell death involved was elusive. In the present study, the effects of TBT on virological and cell death parameters were investigated in HTLV-1-infected immortalized lymphocytes generated by in vitro infection and rendered with or without progressive independence from interleukin-2 as a growth factor. Molecular studies demonstrated that TBT affected HTLV-1 viral gene expression, especially HBZ. TBT confirmed its high cytotoxic potential on the HTLV-1-infected cell lines assayed, especially towards the IL-2-independent HTLV-1-infected cells. Investigation of mechanisms involved in cell death induced by TBT in HTLV-1-infected cells confirmed that caspase 3 and 8 activation, as well as apoptotic response, were relevant. In addition, pyroptosis as well as other unspecifed forms of lytic death presumably contribute to cell death induced by TBT in HTLV-1-infected cells, while a concomitant activation of an autophagic response by this compound seems to mitigate it. Overall, these experimental results outline a particular profile of TBT-induced cell death in HTLV-1-infected cells that is useful for future studies aimed at verifying the real potential of tin-based compounds to contrast diseases caused by HTLV-1.
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