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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. A multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011 was conducted.This survey clarified that half of current patients with ATL were aged over 68 years.

The prognosis of adult T-cell leukemia/lymphoma (ATL) with primary central nervous system (CNS) involvement has been unclear since the advent of new therapies. Recently, we have shown that flow cytometric CD7/CADM1 analysis of CD4 + cells (HAS-Flow) is useful to detect ATL cells that are not morphologically diagnosed as ATL cells. We investigated the role of CNS involvement in ATL using cytology and HAS-Flow by analyzing cerebrospinal fluid (CSF) from 73 aggressive ATL cases. Based on the findings in CSF, the study subjects were classified into CNS + (cytologically malignant, n  = 18), CNS- (cytologically non-malignant and ATL cell population negative in HAS-Flow, n  = 44), and CNS-Micro (cytologically non-malignant and ATL cell population positive in HAS-Flow, n  = 11) groups. As expected, the CNS + group had a shorter overall survival than the CNS- groups ( P  < 0.001). However, the CNS-Micro group showed no adverse impact on overall survival compared to the CNS- group ( P  = 0.506), even without additional CNS-targeted treatments. HAS-Flow also demonstrated clinical utility in the diagnosis of CSF lesions in ATL patients with cerebral white matter lesions and in the detection of ATL cells on post-treatment CSF examination in patients with CNS involvement. Our study demonstrates that ATL with CNS involvement have a poor prognosis and that CSF HAS-Flow is useful to assist in the diagnosis of suspected CNS involvement and to detect ATL cells with high sensitivity after treatment.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan. The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

The human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus discovered to be causative of a human cancer, adult T-cell leukemia. The transforming entity of HTLV-1 has been attributed to the virally-encoded oncoprotein, Tax. Unlike the v-onc proteins encoded by other oncogenic animal retroviruses that transform cells, Tax does not originate from a c-onc counterpart. In this article, we review progress in our understanding of HTLV-1 infectivity, cellular transformation, anti-sense transcription and therapy, 30 years after the original discovery of this virus.

Adult T-cell leukemia/lymphoma develops decades after Human T-lymphotropic virus type 1 (HTLV-1) infection. Factors like proviral load (PVL), soluble interleukin-2 receptors (sIL-2R), and clonality are associated with its pathogenesis. However, a comprehensive assessment using multiple factors of ATL development and progression based on flow cytometry (HAS-Flow) has not been performed. We conducted a 10-year clinical follow-up of 160 asymptomatic people living with HTLV-1 using HAS-Flow, PVL, sIL-2R, and the HTLV-1 integration site identification. The cases were classified into three groups based on cell adhesion molecule 1 (CADM1)-expressing cells by HAS-Flow: Group 1 (≤ 10%, 115 cases), Group 2 (> 10% to ≤ 25%, 33 cases), and Group 3 (> 25%, 12 cases). In the follow-up, no cases in Group 1 developed ATL, while five cases in Group 2 and nine in Group 3 did. Among the developed ATL, one case in Group 2 and six in Group 3 progressed to aggressive ATL. Higher CADM1-expressing cells and sIL-2R levels were linked to earlier ATL development. The HTLV-1 integration site was identified in all aggressive ATL cases. Thus, evaluating CADM1-expressing cells by HAS-Flow, assessing sIL-2R, and identifying the HTLV-1 integration site can better predict ATL development and progression to aggressive ATL.

Both adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by HTLV-1, but concurrent development has been rarely reported. We present the case of a 55-year-old female who developed cranial nerve symptoms after a 20-year history of HAM/TSP. Although multiple white matter lesions were observed on brain magnetic resonance imaging, no abnormalities were seen on a systemic computed tomography scan. Quantitative flow-cytometric analysis of cell populations in the cerebrospinal fluid (CSF) revealed that most of the infiltrating cells were not inflammatory cells, but HTLV-1-infected CD4+ CADM-1+ T-cells completely lacking CD7 expression. As stepwise downregulation of CD7 is correlated with disease progression from HTLV-1 carrier to aggressive ATL, the CSF cells were classified as aggressive ATL; these cells exhibited a more progressed phenotype than those in peripheral blood (PB). HAM/TSP disease activity was estimated to be low. From these and other examinations, we made a diagnosis of acute-type ATL, which unusually developed in the central nervous system at initial onset prior to systemic progression. In ATL cases with a challenging diagnosis, immunophenotypic characterization of CSF and PB is valuable for differential diagnosis and understanding disease status.

Here, we report a rare case of relapsed adult T-cell leukemia-lymphoma (ATL) with evidence of clonal relapse 26 years after initial diagnosis. The patient had been diagnosed with an aggressive form of lymphoma-type ATL 26 years prior and did not receive further ATL treatment for approximately 26 years after achieving complete remission. We used nested PCR to identify the amplification of ATL clone-specific accumulation sites in DNA from hematoxylin and eosin-stained specimens from the patient. Furthermore, the sequence of amplicons obtained from peripheral blood mononuclear cells and lymphoma cells from the previously diagnosed ATL were identical, indicating that a human T-cell leukemia virus-type 1 (HTLV-1)-infected clone identical to the one that recently caused ATL was present in the original lymphoma tissue. Although we were unable to identify this clone as the cause of the previous ATL, the peripheral leukemia cells revealed an ATL clone that was present in the tumor cells of a lymph node diagnosed 26 years earlier. To our knowledge, this is the first report demonstrating survival of HTLV-1-infected clones for a quarter of a century in a patient with recurrent ATL.

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the “iATL-PI,” has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses.

Adult T‐cell leukemia‐lymphoma (ATL) is caused by human T‐cell leukemia virus type 1 (HTLV‐1) infection. Among HTLV‐1 encoded genes, HTLV‐1 bZIP factor (HBZ) and tax are critical for the leukemogenesis of ATL. Adult T‐cell leukemia‐lymphoma needs a long latent period before onset, indicating that both viral genes and alterations (genetic and epigenetic) of the host genome play important roles for leukemogenesis. Viral genes influence genetic and epigenetic changes of the host genome, indicating that the virus is of primary importance in leukemogenesis. HBZ is expressed in all ATL cases, whereas Tax expression is heterogeneous among ATL cases. Different patterns of viral gene expression in tumors are also observed for Epstein‐Barr virus. We propose three subtypes of ATL cases based on Tax expression: high, intermittent, and lost expression. HBZ is detected in all ATL cases. Approximately 25% of all ATL cases lost Tax expression at infection of HTLV‐1, indicating that HBZ is the only viral gene responsible for leukemogenesis in addition to genetic and epigenetic changes of the host genes in these ATL cases. The host immune responses to Tax are also implicated in the heterogeneity of ATL. Thus, ATL is a heterogeneous disease in terms of its viral gene expression, which is important for pathogenesis of this intractable lymphomatous neoplasm. In this review, we describe the heterogeneity of adult T‐cell leukemia‐lymphoma (ATL) in regard to viral gene expression, and propose three subtypes of ATL. These findings lead to an understanding of pathogenesis by human T‐cell leukemia virus type 1 and new therapeutic strategies for ATL.

Background HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms. Methods We analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells. Results Here, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells. Conclusions Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.