Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) Tax‐specific T‐cell exhaustion in HTLV‐1‐infected individuals

Adult T‐cell leukemia/lymphoma (ATL) is caused by Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1), and a higher HTLV‐1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV‐1 Tax‐specific CTL (Tax‐CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV‐1 provirus load in PBMC in both HTLV‐1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = ?0.494, P = .037, n = 18) and ATL patients (Rs = ?0.774, P = .001, n = 15). There was also a significant correlation between the HTLV‐1 provirus load and the percentage of PD‐1‐positive Tax‐CTL in both HTLV‐1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD‐1‐positive Tax‐CTL was inversely correlated with their function in HTLV‐1 AC (Rs = ?0.542, P = .020), and ATL patients (Rs = ?0.639, P = .010). These findings indicate that the function of Tax‐CTL decreased as their programmed cell death protein 1 (PD‐1) levels increased, parallel to the increased HTLV‐1 provirus load in PBMC. We propose that functional Tax‐CTL are crucial for determining the HTLV‐1 provirus load in PBMC, not only in HTLV‐1 AC, but also in ATL, and that PD‐1 expression levels are reliable markers of Tax‐CTL function. Thus, modulating the immunological equilibrium between Tax‐CTL and HTLV‐1‐infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV‐1‐associated disease.     

Advanced human T‐cell leukemia virus type 1 carriers and early‐stage indolent adult T‐cell leukemia‐lymphoma are indistinguishable based on CADM1 positivity in flow cytometry

We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T‐cell leukemia virus type 1 (HTLV‐1) infection. In CD4⁺ cells from peripheral blood, CADM1^?CD7⁺ (P), CADM1⁺CD7^dim (D) and CADM1⁺CD7^? (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV‐1 carriers (AC) progress to indolent adult T‐cell leukemia‐lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4⁺ cells and inverse long PCR (clonality analysis) of FACS‐sorted subpopulations. Almost all AC with a high HTLV‐1 proviral load (>4 copies/100 cells) had a CADM1⁺ (D + N) frequency of >10%. AC with 25% < CADM1⁺ ≤ 50% contained expanded clones similar to smoldering‐type ATL. In many patients in the 25% < CADM1⁺ ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering‐type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high‐risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long‐term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.     

Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways

Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin‐mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1‐dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt‐dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin‐induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin‐mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin‐based therapeutic approaches in cancer cells. © 2010 Wiley‐Liss, Inc.     

Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

Human T‐cell leukemia virus type 1 (HTLV‐1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T‐cell malignancy. HTLV‐1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T‐cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV‐1‐infected T‐cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV‐1‐infected T‐cells. Lentiviral transduction of Tax in a human T‐cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF‐κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV‐2 Tax2 protein reduced the BCL11B protein expression in T‐cells. Seven HTLV‐1‐infected T‐cell lines, including three ATL‐derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T‐cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV‐1‐infected T‐cells; Tax‐mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV‐1‐infected T‐cells.     

Evaluation of two prognostic indices for adult T‐cell leukemia/lymphoma in the subtropical endemic area,Okinawa, Japan

Aggressive adult T‐cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL‐PI and Japan Clinical Oncology Group (JCOG)‐PI, in a cohort from Okinawa. The PIs were originally developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three‐year OS rates for ATL‐PI were 35.9% (low‐risk, n = 66), 10.4% (intermediate‐risk, n = 256), and 1.6% (high‐risk, n = 111), and those for JCOG‐PI were 22.4% (moderate‐risk, n = 176) and 5.3% (high‐risk, n = 257). The JCOG‐PI moderate‐risk group included both the ATL‐PI low‐ and intermediate‐risk groups. ATL‐PI more clearly identified the low‐risk patient subgroup than JCOG‐PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three‐year OS rates for ATL‐PI were 34.5% (low‐risk, n = 42), 9.2% (intermediate‐risk, n = 109), and 12.5% (high‐risk, n = 8). Those for JCOG‐PI were 22.4% (moderate‐risk, n = 95) and 7.6% (high‐risk, n = 64). The low‐risk ATL‐PI group had a better prognosis than the JCOG‐PI moderate‐risk group, suggesting that ATL‐PI would be more useful than JCOG‐PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL‐related deaths in Okinawa, was not a prognostic factor in this study.     

Both mTORC1 and mTORC2 are involved in the regulation of cell adhesion

mTOR is a central controller for cell growth/proliferation and survival. Recent studies have shown that mTOR also regulates cell adhesion, yet the underlying mechanism is not known. Here we found that inhibition of mTOR by rapamycin reduced the basal or type I insulin-like growth factor (IGF-1)-stimulated adhesion of cancer cells. Further research revealed that both mTORC1 and mTORC2 were involved in the regulation of cell adhesion, as silencing expression of raptor or rictor inhibited cell adhesion. Also, PP242, an mTORC1/2 kinase inhibitor, inhibited cell adhesion more potently than rapamycin (mTORC1 inhibitor). Of interest, ectopic expression of constitutively active and rapamycin-resistant mutant of p70 kinase 1 (S6K1) or downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) conferred resistance to rapamycin inhibition of cell adhesion, whereas expression of constitutively hypophosphorylated 4E-BP1 (4EBP1-5A) or downregulation of S6K1 suppressed cell adhesion. In contrast, neither genetic manipulation of Akt activity nor pharmacological inhibition of Akt affected cell adhesion. The results suggest that both mTORC1 and mTORC2 are involved in the regulation of cell adhesion; and mTORC1 regulates cell adhesion through S6K1 and 4E-BP1 pathways, but mTORC2 regulates cell adhesion via Akt-independent mechanism.     

Epidemiological and clinical features of adult T‐cell leukemia–lymphoma in Japan, 2010–2011: A nationwide survey

Adult T‐cell leukemia–lymphoma (ATL) is a mature T‐cell malignancy associated with human T‐cell leukemia virus type 1 (HTLV‐1) infection. Japan is the most endemic country for HTLV‐1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV‐1 carriers spread from endemic areas to non‐endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one‐third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV‐1 carrier status are needed.     

CD4+CADM1+ cell percentage predicts disease progression in HTLV‐1 carriers and indolent adult T‐cell leukemia/lymphoma

We recently took advantage of the universal expression of cell adhesion molecule 1 (CADM1) by CD4⁺ cells infected with HTLV‐1 and the downregulation of CD7 expression that corresponds with the oncogenic stage of HTLV‐1‐infected cells to develop a flow cytometric system using CADM1 versus CD7 plotting of CD4⁺ cells. We risk‐stratified HTLV‐1 asymptomatic carriers (AC) and indolent adult T‐cell leukemia/lymphoma (ATL) cases based on the CADM1⁺ percentage, in which HTLV‐1‐infected clones are efficiently enriched. AC and indolent ATL cases were initially classified according to their CADM1⁺ cell percentage. Follow‐up clinical and flow cytometric data were obtained for 71 cases. In G1 (CADM1⁺ ≤ 10%) and G2 (10% < CADM1⁺ ≤ 25%) cases, no apparent clinical disease progression was observed. In G3 (25% < CADM1⁺ ≤ 50%) cases, five out of nine (55.5%) cases progressed from AC to smoldering‐type ATL. In G4 (50% < CADM1⁺) cases, the cumulative incidence of receiving systemic chemotherapy at 3 years was 28.4%. Our results indicate that the percentage of the CD4⁺CADM1⁺ population predicts clinical disease progression: G1 and G2 cases, including AC cases, are stable and considered to be at low risk; G3 cases, including advanced AC cases and smoldering‐type ATL cases based on the Shimoyama criteria, are considered to have intermediate risk; and G4 cases, which are mainly indolent ATL cases, are unstable and at high risk of acute transformation.     

Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T‐cell leukemia‐derived cells

Carbonic anhydrase IX (CA9) is a membrane‐associated carbonic anhydrase that regulates cellular pH, is upregulated in various solid tumors, and is considered to be a therapeutic target. Here, we describe the essential role of CA9 in the tumorigenicity of cells derived from human adult T‐cell leukemia/lymphoma (ATL). We previously established the highly tumorigenic ST1‐N6 subline from the ATL‐derived ST1 cell line by serial xenotransplantation in NOG mice. In the present study, we first show that CA9 expression is strongly enhanced in ST1‐N6 cells. We then sorted ST1 cells by high or low CA9 expression and established ST1‐CA9^high and ST1‐CA9^low sublines. ST1‐CA9^high cells, like ST1‐N6 cells, were more strongly tumorigenic than ST1‐CA9^low or parental ST1 cells when injected into NOG mice. Knockdown of CA9 with shRNAs suppressed the ability of ST1‐CA9^high cells to initiate tumors, and the tumorigenicity of ST1 cells was significantly enhanced by introducing wild‐type CA9 or a CA9 mutant with deletion of an intracytoplasmic domain. However, a CA9 with point mutations in the catalytic site did not increase the tumorigenicity of ST1 cells. Furthermore, we detected a small population of CA9⁺CD25⁺ cells in lymph nodes of ATL patients. These findings suggest that CA9, and particularly its carbonic anhydrase activity, promotes the tumorigenicity of ATL‐derived cells and may be involved in malignant development of lymphoma‐type ATL.     

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T‐cell leukemia/lymphoma

Adult T‐cell leukemia/lymphoma (ATLL) is a mature T‐cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK‐STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression‐free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.     

High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+) -dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.     

Xenotransplantation elicits salient tumorigenicity of adult T‐cell leukemia‐derived cells via aberrant AKT activation

The transplantation of human cancer cells into immunodeficient NOD/SCID/IL‐2Rγc^null (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T‐cell leukemia‐derived cell lines, ST1‐N6 and TL‐Om1‐N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL‐Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1‐N6 and TL‐Om1‐N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK‐2206 attenuated the progression of tumors induced by ST1‐N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T‐cell leukemia‐derived cells.     

NOTCH1 pathway activating mutations and clonal evolution in pediatric T‐cell acute lymphoblastic leukemia

Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole–exome sequencing in 30 pediatric T‐ALL cases, among which 11 diagnosis‐relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon–based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine–rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non–relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis‐relapse samples, we identified NOTCH1 “switching” characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another NOTCH1 “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T‐ALL. Despite the limitations of having a small sample size and a non–minimal residual disease–based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T‐ALL.     

Cadmium‐coordinated supramolecule suppresses tumor growth of T‐cell leukemia in mice

Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal‐coordinating ability has been postulated to contribute to the cytotoxic effects of anti‐tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p‐alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium‐coordinated thiacalix[4]arene tetrasulfate (TC4ATS‐Cd) exhibits an anti‐proliferative effect against T‐cell leukemia cells. Cadmium exhibited cytotoxicity with IC₅₀ values ranging from 36 to 129 μM against epithelia‐derived cancer cell lines, while TC4ATS‐Cd elicited no significant cytotoxicity (IC₅₀ > 947 μM). However, a number of T‐cell leukemia cell lines exhibited marked sensitivity to TC4ATS‐Cd. In Jurkat cells, toxicity of TC4ATS‐Cd occurred with an IC₅₀ of 6.9 μM, which is comparable to that of 6.5 μM observed for cadmium alone. TC4ATS‐Cd induced apoptotic cell death through activation of caspase‐3 in Jurkat cells. In a xenograft model, TC4ATS‐Cd (13 mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS‐Cd‐treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium‐treated mice. These results suggest that cadmium‐coordinated supramolecules may have therapeutic potential for treatment of T‐cell leukemia.     

Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD

T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.     

Induction of apoptosis by HBI‐8000 in adult T‐cell leukemia/lymphoma is associated with activation of Bim and NLRP3

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive T‐cell malignancy caused by human T‐cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti‐chemokine (C‐C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI‐8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T‐cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI‐8000 on ATL‐derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI‐8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI‐8000‐induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI‐8000‐induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI‐8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI‐8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway.