scholarly journals Current Clinico-Epidemiological Characteristics of Adult T-Cell Leukemia-Lymphoma (ATL) Based on the 11th Nationwide Survey in Japan

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5034-5034
Author(s):  
Kisato Nosaka ◽  
Masako Iwanaga ◽  
Kenichi Ishizawa ◽  
Yoji Ishida ◽  
Kaoru Uchimaru ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Features ◽  
Research Funding ◽  
Age At Diagnosis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Subtype Classification ◽  
Epidemiological Features ◽  
Lymphoma Subtype

Abstract Introduction: Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-cell lymphomacaused by human T-lymphotropic virus type I (HTLV-1), which is endemic in Japan. Only a small percentage of HTLV-1 carriers infected through breast-feeding develop the disease. Previous nationwide surveys during 1980s-2000s in Japan provided a comprehensive view on the clinio-epidemiological profiles of ATL, including the establishment of the subtype-classification (i.e., the Shimoyama criteria: acute, lymphoma, chronic, and smoldering type) based on the diversity of the clinical features and prognosis. Treatment strategies have been developed by the subtype-classification; watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive ATL. The aim of this 11th survey is to characterize the current clinio-epidemiological features of ATL in Japan in the light of previous surveys. Methods: In 2013-14, we conducted an anonymous, cross-sectional, hospital-based survey of patients with ATL who were newly diagnosed during 2010-2011 across Japan. First, we asked 2500 hospitals with departments of hematology and dermatology to participate in this survey, and then we sent questionnaires to 128 participating hospitals to accumulate data of ATL. Skilled five hematologists reviewed the data of each questionnaire sheet, and the agreements of ATL diagnosis including the subtypes between the central review and participating hospitals were evaluated using Kappa statistics. Most of the collected data were analyzed by descriptive statistics. Results: A total of 996 ATL patients were registered; of these, 41 were eliminated because of the insufficient information for the diagnosis of ATL. Overall diagnostic agreement on subtype of ATL was substantial, with a kappa value 0.71 (standard error, 0.021); most of the disagreement was within aggressive/indolent category, acute vs. lymphoma types or acute vs. unfavorable chronic types. Among the 955 evaluable patients (M/F ratio, 1.12), 70% were diagnosed in the southwest region of Japan (Kyusyu/Okinawa) where HTLV-1 is endemic, which was consistent with the past surveys. The mean age at diagnosis was 68.3 years (median 68.8, range 24.7-100.3), which was significantly higher than 60.3 years in 1994-1995 and 57.7 years in 1986-1987. The proportion of ATL patients aged over 65 years was 79 % in this survey (whereas, 48% in the 1990-1991 survey), which indicates that the allo-HSCT is not applicable to the majority of current ATL patients in Japan. The proportion of acute, lymphoma, chronic, and smoldering types was 48, 28, 10 and 13%, respectively. The proportion of smoldering and chronic types tended to be greater than previous surveys (7% and 10% in the 1988-1997 surveys combined). The proportion of subtype by age group in this survey showed that the older in age at diagnosis are, the higher proportion of lymphoma subtype (10% in those aged younger than 40 years, 20% in those 50-59, and 31% in those 70 years or older. Discussion: This 11th survey revealed several clinio-epidemiological features of current ATL in Japan different from those in past two decades. First, a considerably increasing proportion of elderly ATL patients were diagnosed, which may be expected from a recent distribution of nationwide HTLV-1 carriers in Japan (Satake, et al, 2011). Second, there is an increasing tendency in the proportion of indolent types of ATL. This may be partly influenced by participation of the dermatology departments for the first time, because early phase of ATL localized in skin were frequently diagnosed in the dermatology department. Third, the proportion of lymphoma subtype was increased with age, which suggests that aging-related unknown mechanisms may affect the subtype distribution. More detailed analysis and subsequent surveys are planned to further evaluate clinical features and the efficacy of modern therapies on prognosis of ATL. Disclosures Ishizawa: Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Pfizer: Speakers Bureau. Ishida:Bristol-Myers Squibb: Honoraria. Ishida:Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Celgene K.K.: Other: Research Funding to my institution. Tobinai:Gilead Sciences: Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

scholarly journals Epidemiology, Clinical Features, and Outcome of HTLV-1-Related Adult T-Cell Leukemia/Lymphoma in Latin America: A Study from the Latin American Group of Lymphoproliferative Disorders (GELL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-21
Author(s):  
Luis E Malpica Castillo ◽  
Daniel J Enriquez ◽  
Denisse A. Castro ◽  
Camila Peña ◽  
Henry Idrobo ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Clinical Features ◽  
Latin American ◽  
Research Funding ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
First Line ◽  
Advisory Committees ◽  
Adult T Cell Leukemia

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by the Human T-cell Leukemia Virus Type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwide and is most endemic in Southwestern Japan, the Caribbean basin, South America, and Western Africa. In Latin America (LA), Peru and Brazil have the highest prevalence of HTLV-1-related diseases, however, data on ATLL in other LA countries is scarce. ATLL carries a dismal prognosis and is essentially incurable by conventional drugs. We describe the epidemiology, clinical features, treatment, and disease outcome of ATLL encountered in 11 countries in LA. METHODS: We retrospectively analyzed patients (pts) diagnosed with ATLL between January 1995 and December 2019. ATLL cases were classified according to the Shimoyama criteria into acute (A), lymphomatous (L), chronic (C) and smoldering (S). Treatment approaches used as first-line therapy were: 1) chemotherapy alone; 2) combined chemotherapy with zidovudine/interferon-alpha (AZT-IFN); and 3) AZT-IFN alone, as previously done with Miami cohort (Malpica and Ramos et al. Blood Advances 2018). Treatment response was assessed according to Tsukasaki et al. (JCO 2009) criteria. To be classified as complete response (CR), partial response and stable disease, these had to persist for a period of at least 4 weeks. Survival curves were estimated using the Kaplan-Meier method and Log rank test. RESULTS: A total of 253 pts with ATLL were identified. Two hundred twenty six pts (L=122, A=73, C=26, S=5) had sufficient data for analysis. Demographic and clinical features are shown in Figure 1 and Table 1. Median age at diagnosis was 57 years, with a female predominance in A (58%) and S (100%) types. Most ATLL pts were from Peru (n=159, 63%) followed by Chile (n=44, 17%), Argentina (n=20, 8%) and Colombia (n=17, 7%). B symptoms were high present in A, L and C types (73%, 72%, 58% vs. 8% S type, respectively, p=0.011). Hypercalcemia was highly associated with A type (57% vs. L 27%, p=0.014). The PIT score yielded to a more aggressive risk classification compared to the IPI score (high-risk: 55% vs. 29%, respectively, p<0.001). Strongyloidiasis (n=5) and pneumocystis jirovecii pneumonia (n=5) were the most commonly observed co-infections at diagnosis. Commonly affected extranodal sites other than bone marrow in all subtypes were skin 25% (n=63) and liver 9% (n=24). The therapy approach used during the first 2 therapy evaluations are summarized in Table 2. The median survival (MS) times were 4.3 months, 7.9 months, 21.1 months, and not reached for A, L, C and S form, with 4-year survival of 8%, 22%, 40% and 80%, respectively (Figure 2). First-line AZT-IFN resulted in overall response (OR) rate of 63% (CR 24%) for A (n=8) and 75% (CR 50%) for L (n=8), respectively (Table 3). The OR rates after first-line multi-agent chemotherapy alone for A vs. L were 21% (CR 8%) and 41% (CR 29%), respectively (Table 3). The most commonly used regimens were CHOP/CHOP-like (n=117, 59%) and CHOEP (n=40, 20%) regimens with OR rates of 29% (CR 12%) and 60% (CR 42%), respectively (Table 3). Progression-free survival (PFS) rates in pts with aggressive ATLL who achieved CR after chemotherapy vs. AZT-IFN (alone or in combination with chemotherapy) were 2.8 months vs. 30.4 months for A (n=8) type and 67.1 months vs. 17.7 months for L (n=30) type, respectively (Figure 3). Only 2 pts with L type underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) with PFS of 12 and 17 months (Table 4). CONCLUSION: ATLL continues to carry a dismal outcome with conventional therapies thus urging the development of novel approaches. Our study found that Latin American ATLL variant presents at a younger age, has a female predominance, high incidence of L type, low incidence of indolent types and lower survival rates, suggesting that Latin American ATLL variant presents earlier and more aggressively than in Japanese pts. AZT-IFN produced durable responses in A type patients who achieved CR as compared to chemotherapy alone. Chemotherapy responses were more durable in L types who achieved CR as compared to A type. In conclusion, in the management of aggressive ATLL, chemotherapy remains the preferred choice for L type (with consideration of allo-HSCT upfront), while AZT-IFN is a good option to attempt for A type upfront. Figure Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Altamirano:Hospital Nacional Guillermo Almenara Irigoyen: Other: Servicio de Hematologia. Perini:Abbvie: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria. Castillo:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; TG Therapeutics: Research Funding; Kymera: Consultancy; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Ramos:NIH: Research Funding. Villela:Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.

Clinical features at transformation in adult T-cell leukemia–lymphoma with smoldering and chronic types

2019 ◽  
Vol 109 (4) ◽  
pp. 402-408 ◽  
Author(s):  
Hiroaki Taniguchi ◽  
Yoshitaka Imaizumi ◽  
Yumi Takasaki ◽  
Jun Nakashima ◽  
Takeharu Kato ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Features ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

Clinical features of OKT4+/OKT8+ adult T-cell leukemia

1985 ◽  
Vol 9 (11) ◽  
pp. 1353-1359 ◽  
Author(s):  
Kazuo Tamura ◽  
Toshihide Unoki ◽  
Kimitaka Sagawa ◽  
Yatsuki Aratake ◽  
Toshio Kitamura ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Features ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2643-2643 ◽  
Author(s):  
Keisuke Kataoka ◽  
Yasunobu Nagata ◽  
Akira Kitanaka ◽  
Jun-ichirou Yasunaga ◽  
Masako Iwanaga ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Genetic Profiling ◽  
Adult T Cell Leukemia ◽  
Disease Subtype ◽  
The Impact

Abstract Adult T-cell leukemia/lymphoma (ATL) is a distinct subtype of peripheral T-cell neoplasms associated with human T-cell leukemia virus type-1 retrovirus. ATL includes a heterogeneous group of patients in terms of pathological and clinical features as well as prognosis, suggesting the presence of underlying molecular pathogenesis that could explain such heterogeneity among patients. Recently, we performed an integrated molecular analysis of a large number of ATL cases and delineated a comprehensive registry of gene mutations and other genetic/epigenetic lesions in ATL. In this study, we investigated possible correlations between these genetic/epigenetic lesions and clinical/pathological phenotypes in a large set of ATL patients, with a special focus on the impact of mutations and copy number alterations (CNAs) on clinical outcome. We analyzed a total of 361 ATL samples, including acute (n = 192), lymphoma (n = 66), chronic (n = 89), and smoldering (n = 14) subtypes, for recurrent mutations and CNAs. Each subtype had characteristic genetic/epigenetic features, suggesting a distinct molecular pathogenesis therein. Aggressive (acute and lymphoma) subtypes were characterized by a higher number of mutations and CNAs including focal amplifications/deletions, hyperploid status, and CIMP phenotype, compared with indolent (chronic and smoldering) tumors. Two mutations (TP53 and IRF4) and eight focal deletions involving 1p13 (CD58), 6p21 (HLA-B), 9p21 (CDKN2A), 10p11 (CCDC7), 13q32 (GPR183), 16q23 (WWOX), 17p13 (TP53), and 19q13 (CEBPA), were more common in aggressive ATL than in indolent ATL. In contrast, showing a similar mutational distribution to those found in large granular lymphocytic leukemia, STAT3 mutations were characteristic of the indolent diseases. Gene set enrichment analysis of RNA-seq data showed a significant enrichment of MYC pathway and genes regulating cell cycle and DNA repair in upregulated genes in aggressive ATL. Next, we assessed the impact of mutations and CNVs on prognosis among 215 ATL cases, for which survival data were available. In the entire cohort, mutation in CCR4 and IRF4, focal amplification in 9p24 (CD274) and 14q32 (BCL11B), and focal deletion in 9p21 (CDKN2A) were found to be significant predictors of poor overall survival, after adjustment for disease subtype and age. Multivariate analysis revealed that disease subtype (aggressive vs. indolent) was the most significant predictor of clinical outcome in ATL. Subsequent multivariate analysis according to disease subtype showed that within the patients with aggressive ATL, older age (≥ 70 years), CCR4 mutations, and 9p24 amplification were independently associated with an adverse outcome. Based on the number of the risk factors they owned, patients with aggressive ATL were classified into three categories showing marked difference in 3-year overall survival (OS) (P < 0.001): those with no risk factors (OS, 32%), with one risk factor (18%), and with two or more (0%). Among the patients with indolent ATL, we found IRF4 and TP53 mutations, 9p24 amplification, and deletions in 9p21 and 10p11 were independently associated with reduced survival. Interestingly, these alterations, except for 9p24 amplification, were also identified as genes more frequent in aggressive ATL. More importantly, based on these risk factors, the patients with indolent ATL can be classified into two categories showing very different prognostic profiles: patients with no risk factors (OS, 89%) and those with one or more risk factors (21%) (P < 0.001, HR = 16.8, 95% CI:5.4-52.5), suggesting that patients with indolent ATL having a genetic feature of the aggressive subtypes might genetically and biologically represent a distinct subset, which should be better managed as having an aggressive disease. Among these poor prognostic factors, 9p24 amplification and CCR4 mutation are especially interesting, because these lesions might be plausible targets of available agents, including anti-PD1/PD-L1 and anti-CCR4 antibodies. In conclusion, based on the comprehensive genetic profiling, we demonstrated that the known subtypes of ATL can be further classified into genetically and biologically distinct subsets of tumors characterized by discrete sets of genetic lesions and substantially different prognosis. Our results suggest that molecular profiling can improve the prediction of prognosis in ATL patients and better guide therapy. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Shin-bio: Honoraria; Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

Frequent Activating Somatic Alterations in T-Cell Receptor / NF-κb Signaling in Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 113-113 ◽  
Author(s):  
Keisuke Kataoka ◽  
Yasunobu Nagata ◽  
Akira Kitanaka ◽  
Yuichi Shiraishi ◽  
Jun-ichirou Yasunaga ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Receptor ◽  
T Cell Leukemia ◽  
Rna Seq ◽  
Cell Leukemia ◽  
Tcr Signaling ◽  
Adult T Cell Leukemia ◽  
Somatic Alterations

Abstract Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm of largely unknown genetic basis, which is associated with human T-cell leukemia virus type-1 (HTLV-1) infection. To delineate a genetic landscape of somatic alterations in ATL, we have performed an integrated genetic study, in which whole-genome/exome (WGS/WES) and transcriptome sequencing (RNA-seq) was performed for a cohort of 83 paired ATL samples, followed by extensive validation using targeted sequencing of detected mutations in 370 follow-up samples. A striking feature of driver lesions in ATL was their strong enrichment in the components of T-cell receptor (TCR) / NF-κB pathway. Accounting for more than 90% of ATL cases, these lesions were characterized by the predominance of activating alterations, including hotspot missense mutations in PLCG1 (36%), PRKCB (33%), CARD11 (24%), VAV1 (18%), IRF4 (14%) and FYN (4%). Among these, most frequently mutated was PLCG1, which encodes phospholipase C γ1 (PLCγ1), a key regulator of the proximal TCR signaling. Besides the S345F and S520F mutations recently reported in cutaneous T-cell lymphoma, we identified an additional hotspot mutations (R48W, E1163K, and D1165H). The second most frequently mutated gene was PRKCB, encoding a member of the protein kinase C (PKC) family of proteins (PKCβ), a pivotal signaling molecule downstream of PLCγ. The frequent mutations of PKCβ were unexpected, because it is PKCθ that has been implicated in TCR signaling, whereas PKCβ has been more focused in the context of B-cell receptor signaling. Approximately 93% of the PRKCB mutations were confined to the catalytic domain with a prominent hotspot at D427, suggesting gain-of-function nature of these mutations. Consistent with this, when transduced with the D427N PKCβ mutant, HEK293T and/or Jurkat cells showed increased membrane translocation after PMA/Ionomycin-stimulation, enhanced IKK phosphorylation and p65 nuclear translocation, and augmented NF-κB transcription, compared to wild-type PKCβ-transduced cells. Thus, these PRKCB mutations are the first activating mutations of this family identified in human cancers. Downstream to PKC lies CARD11, a scaffolding protein required for antigen receptor-induced NF-κB activation. Although previously reported in B-cell lymphomas, CARD11 mutations were more common in ATL (24%). In B-cell lymphomas, mutations are largely limited to the coiled-coil (CC) domain, whereas in ATL, they were clustered not only within the CC domain, but also within the PKC-responsive inhibitory domain, showing a prominent mutational hotspot at E626. The inhibitory domain has been implicated in autoinhibition, whose deletion leads to constitutive activation of CARD11. Intriguingly, WGS identified small intragenic deletions confined to this domain (exons 14-17) in 4 cases (8%) without canonical mutations, and RNA-seq confirmed the skipping of the corresponding exons in these cases. Remarkably, CARD11 mutation significantly co-occurred with PRKCBmutations, suggesting potential functional synergism between these lesions. Actually, overexpression of wild-type CARD11 induced NF-κB activation, which was further augmented by E626K mutation. Similarly, when both CARD11 (E626K) and PRKCB (D427N) mutants were co-expressed, more enhanced NF-κB activation was observed. RNA-seq and follow-up RT-PCR screening also identified novel gene fusions in TCR / NF-κB pathway: five CTLA4-CD28 and three ICOS-CD28 fusions were observed in seven (7%) of the 105 cases examined, of whom one patient carried both chimeric fusions. WGS revealed tandem duplications of 2q33.2 segments containing CD28, CTLA4, and ICOS, compatible with the corresponding fusion transcripts. B7/CD28 co-signaling molecules, including CD28, CTLA4, and ICOS co-receptors, play pivotal roles in positive and negative regulations of TCR signaling. All the predicted chimeric proteins had the cytoplasmic part of CD28, and are expected to be expressed under the control of the regulatory element of CTLA4 or ICOS, likely leading to prolonged expression of CD28 co-stimulator. Our findings suggest that deregulated TCR / NF-κB pathway caused by genetic alterations is a hallmark of ATL pathogenesis. The predominance of gain-of-function mutations in this pathway offers good opportunities for exploiting these mutations for the targets of novel drugs to better manage patients. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Chugai: Honoraria, Research Funding; Shin-bio: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

Identification of Super-Enhancer-Associated Cancer Genes Provides Novel Therapeutic Targets in Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2720-2720
Author(s):  
Regina Wan Ju Wong ◽  
Phuong Thi Ngoc Cao ◽  
Wei Zhong Leong ◽  
Alice Wei Yee Yam ◽  
Tinghu Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Research Funding ◽  
Rnai Screen ◽  
T Cell Leukemia ◽  
Cancer Genes ◽  
Cell Leukemia ◽  
Pol Ii ◽  
Adult T Cell Leukemia ◽  
Super Enhancer

Abstract Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive lymphoproliferative disorder that arises from mature T-lymphocytes. The onset of this disease is preceded by a long period of latency of 30 to 50 years, indicating that multiple cellular oncogenic mechanisms after HTLV-1 infection are involved in its pathogenesis. Notably, the recent genome-wide sequencing study revealed that a large number of genetic and chromosomal abnormalities are found in ATL. However, there is still a lack of functional evidence of those genetic abnormalities in the ATL pathogenesis due to a large mutation burden per sample and a high genetic heterogeneity across different ATL samples. Super-enhancers are clusters of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 (H3K27Ac) using ChIP-seq analysis. Recently, rapidly accumulating evidences have shown that super-enhancers are often enriched at cancer genes in various malignancies. Therefore, the identification of such enhancers would pinpoint crucial genes, on which cancer/leukemia cells depend on in the acquisition of hallmark capabilities in cancer. Here, we performed a super-enhancer profiling combined with gene expression analysis followed by a loss-of-function RNA interference (RNAi) screen in ATL cells. By H3K27Ac ChIP-seq, we found that super-enhancers are frequently enriched at the genes involved in T-cell activation and T-cell signaling pathway, including CD2, IL2RA/CD25 and TNFRSF8/CD30, both in ATL and normal mature T-cells, confirming the origin of ATL cells. RNA Polymerase II (Pol II) metagene analysis demonstrated that super-enhancer-associated genes showed higher Pol II signal at the transcriptional start site (TSS) to transcriptional end site (TES) than the typical enhancer-associated genes. These super-enhancer-associated genes are sensitive to the THZ1 small-molecule CDK7 inhibitor treatment. Additionally, by a RNAi screen, we identified several genes including CCR4, which are highly activated in primary ATL samples and are required for the growth of ATL cell line. THZ1 treatment efficiently downregulated the expression of these genes and resulted in cell growth inhibition. Individual knockdown analysis demonstrated that a loss of each of these proteins significantly blocked the growth of multiple ATL cell lines but not T-ALL cells. Taken together, our study identified critical cancer genes in ATL based on a super-enhancer profiling. This study is the first to utilize a combinatorial approach of super-enhancer profiling, gene analysis after THZ1 treatment and functional RNAi screening to identify genes that are aberrantly activated and required in cancer. Disclosures Iida: Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy. Ishida:Bayer Pharma AG: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding.

scholarly journals HTLV-1-Associated Lymphoma Presented as Massive Lymphadenopathy

2021 ◽  
Vol 9 ◽  
pp. 232470962110132
Author(s):  
Pei Ting Chen ◽  
David Onukogu ◽  
Gregory Gotlieb ◽  
Rashid Chaudhry ◽  
Vijay Jaswani ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Features ◽  
Bone Lesions ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Massive Lymphadenopathy ◽  
Human T Cell

Adult T-cell leukemia/lymphoma is an aggressive T-cell malignancy caused by the long-term infection of human T-cell lymphotropic virus type 1 (HTLV-1). Our understanding of clinical features still largely relies on the Shimoyama classification developed 30 years ago, which described the 4 clinical subtypes (the smoldering, chronic, lymphoma, and acute types) based on the manifestations of lymphocytosis, elevated lactate dehydrogenase, hypercalcemia, lymphadenopathy, and involvement of the skin, lung, liver, spleen, central nervous system, bone, ascites, pleural effusion, and gastrointestinal tract. HTLV-1-associated lymphoma has a variety of presentations but the presentation of massive lymphadenopathy and compression symptoms is rare and has not been emphasized in the literature. In this article, we describe 2 cases of adult T-cell leukemia/lymphomas that presented with massive cervical nodes or mediastinal nodes with compressing symptoms as the major presenting clinical features. Clinicians should remain aware of this type of presentation by HTLV-1-associated lymphoma, especially in patients who came from endemic areas, even if not all clinical features are present and particularly with hypercalcemia and lytic bone lesions.

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