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Whole-genome landscape of adult T-cell leukemia/lymphoma.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

SUBMITTER: Kogure Y

PROVIDER: S-EPMC8854674 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Whole-genome landscape of adult T-cell leukemia/lymphoma.

Kogure Yasunori Y Kameda Takuro T Koya Junji J Yoshimitsu Makoto M Nosaka Kisato K Yasunaga Jun-Ichirou JI Imaizumi Yoshitaka Y Watanabe Mizuki M Saito Yuki Y Ito Yuta Y McClure Marni B MB Tabata Mariko M Shingaki Sumito S Yoshifuji Kota K Chiba Kenichi K Okada Ai A Kakiuchi Nobuyuki N Nannya Yasuhito Y Kamiunten Ayako A Tahira Yuki Y Akizuki Keiichi K Sekine Masaaki M Shide Kotaro K Hidaka Tomonori T Kubuki Yoko Y Kitanaka Akira A Hidaka Michihiro M Nakano Nobuaki N Utsunomiya Atae A Sica R Alejandro RA Acuna-Villaorduna Ana A Janakiram Murali M Shah Urvi U Ramos Juan Carlos JC Shibata Tatsuhiro T Takeuchi Kengo K Takaori-Kondo Akifumi A Miyazaki Yasushi Y Matsuoka Masao M Ishitsuka Kenji K Shiraishi Yuichi Y Miyano Satoru S Ogawa Seishi S Ye B Hilda BH Shimoda Kazuya K Kataoka Keisuke K

Blood 20220201 7

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not s ...[more]

PMID: 34695199

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Project description:Adult T cell leukemia-lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with the human T cell leukemia virus type I (HTLV-I) retrovirus. ATL carries a dismal prognosis. ATL classifies into four subtypes (acute, lymphoma, chronic, and smoldering) which display different clinical features, prognosis and response to therapy, hence requiring different clinical management. Smoldering and chronic subtypes respond well to antiretroviral therapy using the combination of zidovudine (AZT) and interferon-alpha (IFN) with a significant prolongation of survival. Conversely, the watch and wait strategy or chemotherapy for these indolent subtypes allies with a poor long-term outcome. Acute ATL is associated with chemo-resistance and dismal prognosis. Lymphoma subtypes respond better to intensive chemotherapy but survival remains poor. Allogeneic hematopoietic stem cell transplantation (HSCT) results in long-term survival in roughly one third of transplanted patients but only a small percentage of patients can make it to transplant. Overall, current treatments of aggressive ATL are not satisfactory. Prognosis of refractory or relapsed patients is dismal with some encouraging results when using lenalidomide or mogamulizumab. To overcome resistance and prevent relapse, preclinical or pilot clinical studies using targeted therapies such as arsenic/IFN, monoclonal antibodies, epigenetic therapies are promising but warrant further clinical investigation. Anti-ATL vaccines including Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients. Finally, based on the progress in understanding the pathophysiology of ATL, and the risk-adapted treatment approaches to different ATL subtypes, treatment strategies of ATL should take into account the host immune responses and the host microenvironment including HTLV-1 infected non-malignant cells. Herein, we will provide a summary of novel treatments of ATL in vitro, in vivo, and in early clinical trials.

Dataset Information

Whole-genome landscape of adult T-cell leukemia/lymphoma.

Publications

Whole-genome landscape of adult T-cell leukemia/lymphoma.

Similar Datasets

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