North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies

Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanes...

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Bibliographic Details
Published in:	Blood 2018-10, Vol.132 (14), p.1507-1518
Main Authors:	Shah, Urvi A., Chung, Elaine Y., Giricz, Orsi, Pradhan, Kith, Kataoka, Keisuke, Gordon-Mitchell, Shanisha, Bhagat, Tushar D., Mai, Yun, Wei, Yongqiang, Ishida, Elise, Choudhary, Gaurav S., Joseph, Ancy, Rice, Ronald, Gitego, Nadege, Parrish, Crystall, Bartenstein, Matthias, Goel, Swati, Mantzaris, Ioannis, Shastri, Aditi, Derman, Olga, Binder, Adam, Gritsman, Kira, Kornblum, Noah, Braunschweig, Ira, Bhagat, Chirag, Hall, Jeff, Graber, Armin, Ratner, Lee, Wang, Yanhua, Ogawa, Seishi, Verma, Amit, Ye, B. Hilda, Janakiram, Murali
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Antimetabolites, Antineoplastic - therapeutic use Apoptosis - drug effects Decitabine - therapeutic use E1A-Associated p300 Protein - genetics Epigenesis, Genetic Female Humans Japan - epidemiology Leukemia-Lymphoma, Adult T-Cell - diagnosis Leukemia-Lymphoma, Adult T-Cell - drug therapy Leukemia-Lymphoma, Adult T-Cell - epidemiology Leukemia-Lymphoma, Adult T-Cell - genetics Lymphoid Neoplasia Male Middle Aged Mutation Rate Prognosis Transcriptome Tumor Suppressor Protein p53 - genetics United States - epidemiology
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Summary:	Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-κB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors. •North American ATLL has a distinct genomic landscape with a high frequency of prognostic epigenetic mutations, including EP300 mutations.•ATLL samples with mutated EP300 have compromised p53 function and are selectively sensitive to decitabine treatment. [Display omitted]
ISSN:	0006-4971 1528-0020