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Abstract Background Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Methods We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation. Results Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. Conclusions These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.

Objectives: Adult T‐cell leukemia/lymphoma (ATL) is an intractable T‐cell malignancy caused by long‐term infection with human T‐cell leukemia virus type‐1 (HTLV‐1). While ATL pathogenesis has been associated with HTLV‐1‐derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined. Methods: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL. Results: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11‐0.68). Despite being reported in cutaneous T‐cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF‐κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF‐κB activity and significantly increased IL‐2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax. Conclusions: We identified, and functionally validated, a novel gain‐of‐function mutation in patients with aggressive ATL. During TCR activation by Tax or gain‐of‐function mutations, RLTPR Q575E selectively upregulates NF‐κB signaling and may exert oncogenic effects on ATL pathogenesis. [ABSTRACT FROM AUTHOR]

Despite the efficacy of combination chemotherapy with arsenic trioxide (ATO), interferon α (IFN) and zidovudine (AZT) for adult T cell leukemia/lymphoma (ATL), the precise mechanism underlying this combination treatment effect is unknown. In the present study, ATO/IFN/AZT was examined in an ATL leukemic cell line (S1T, non-Tax expressing), a human T-lymphotropic virus 1 (HTLV-1)-infected cell line (MT2, Tax-expressing) and primary ATL cells from patients with acute and chronic ATL. IFN/AZT marginally inhibited MT2 cell proliferation, but substantially inhibited S1T cell proliferation. IFN/AZT increased the cleavage of numerous caspases and PARP in S1T cells, and regulated the signal transducer and activator of transcription 1 and nuclear factor-κB signaling pathway. These effects represent the potential anti-ATL mechanisms of INF/AZT in vitro. In addition, the combination of ATO and IFN/AZT demonstrated synergistic effects on S1T cells. Therefore, the Tax-independent mechanism underlying the anti-ATL effect of ATO must be further elucidated. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). Miscellaneous host immune surveillance systems control T-cell growth/leukemogenesis during HTLV-1 infection. We characterized CD70 and CD27 expression on lymphocytes of HTLV-1 carriers and patients with ATL (study approved by the local Medical Ethical Committee). High CD70 expression was observed on CD4 + CD25+ T cells from patients with acute-type ATL, while patients with smoldering- or chronic-type ATL and HTLV-1 carriers exhibited lower expression. Furthermore, significantly higher CD27 expression was observed on HTLV-1-specific CTLs. We found an association between CD70 expression on CD4 + T cells and HTLV-1 infection; increased CD70 expression was observed after exposure to Tax. Moreover, addition of anti-CD70 antibodies enhanced the CD107a surface mobilization of HTLV-1 Tax-specific CTLs following Tax-peptide stimulation in the PBMCs of carriers. These data demonstrate the important role of the CD70/CD27 axis in immune responses in HTLV-1 carriers and ATL patients. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy caused by the human T-cell lymphotropic virus, type I and it has an extremely poor prognosis. A 66-year-old man with severe hepatic damage, massive pleural effusion and ATL cell infiltration-induced ascites was referred to our department. Reduced-intensity cytotoxic chemotherapy was attempted, but could not continue due to persistent hyperbilirubinemia. Laboratory results also showed elevated lactate dehydrogenase (LDH) and serum albumin levels were profoundly decreased. A humanized monoclonal antibody against chemokine receptor type 4 (CCR4), mogamulizumab (Moga), was thereby challenged and it successfully resolved the hepatic damage. Finally, a standard dose of chemotherapy could be administered, and it induced a complete remission. The patient is still in remission more than three years after the final dosage of standard chemotherapy. These results indicate that Moga, whose pharmacokinetics are not significantly influenced by hepatic function or serum albumin, could be a promising treatment option for patients with ATL complicated by severe hepatic damage due to infiltration of ATL cells.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). Miscellaneous host immune surveillance systems control T-cell growth/leukemogenesis during HTLV-1 infection. We characterized CD70 and CD27 expression on lymphocytes of HTLV-1 carriers and patients with ATL (study approved by the local Medical Ethical Committee). High CD70 expression was observed on CD4 + CD25+ T cells from patients with acute-type ATL, while patients with smoldering- or chronic-type ATL and HTLV-1 carriers exhibited lower expression. Furthermore, significantly higher CD27 expression was observed on HTLV-1-specific CTLs. We found an association between CD70 expression on CD4 + T cells and HTLV-1 infection; increased CD70 expression was observed after exposure to Tax. Moreover, addition of anti-CD70 antibodies enhanced the CD107a surface mobilization of HTLV-1 Tax-specific CTLs following Tax-peptide stimulation in the PBMCs of carriers. These data demonstrate the important role of the CD70/CD27 axis in immune responses in HTLV-1 carriers and ATL patients.

Background: Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid., Materials and Methods: Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated., Results: The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone., Conclusion: The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.