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

Urvi A. Shah, Elaine Y. Chung, Orsi Giricz, Kith Pradhan, Keisuke Kataoka, Shanisha Gordon-Mitchel, Tushar D. Bhagat, Yun Mai, Yongqiang Wei, Elise Ishida, Gaurav S. Choudhary, Ancy Joseph, Ronald Rice, Nadege Gitego, Crystall Parrish, Matthias Bartenstein, Swati Goel, Ioannis Mantzaris, Aditi Shastri, Olga DermanAdam Binder, Kira Gritsman, Noah Kornblum, Ira Braunschweig, Chirag Bhagat, Jeff Hall, Armin Graber, Lee Ratner, Yanhua Wang, Seishi Ogawa, Amit Verma, B. Hilda Ye, Murali Janakiram

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1507-1518
Number of pages12
JournalBlood
Volume132
Issue number14
DOIs
StatePublished - Oct 4 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by Leukemia & Lymphoma Society Translational Research grant 6471-15 (B.H.Y.) and AIDS Malignancy Consortium grant UM1CA121947 (M.J.). E.Y.C. is supported by the Harry Eagle Scholarship from the Department of Cell Biology, Albert Einstein College of Medicine. U.A.S. is supported by the hematology/oncology fellowship program, Montefiore Medical Center and Jacobi Medical Center.

Funding Information:
The authors thank Thomas Waldmann and Michael Petrus (National Institutes of Health/National Cancer Institute, Bethesda, MD), Naomichi Arima (Kagoshima University, Kagoshima, Japan) for the gift of the Japanese ATLL cell lines, and Naomichi Arima for valuable advice on establishing long-term ATLL cultures. Flow cytometry analyses were performed at the Albert Einstein College of Medicine Flow Cytometry facility, which is supported by National Institutes of Health National Cancer Institute Cancer Center Support grant P30CA013330. FACS sorting was performed at the Einstein Human Stem Cell FACS and Xenotransplantation Facility, which is supported by a grant from the New York State Department of Health (NYSTEM Program) for the shared facility (C029154). The authors also acknowledge the Einstein Epi-genomics Core for assistance with RNA-seq analysis. The authors thank Xiaoxin Ren for technical assistance with isolating CD4 cells from control samples, as well as our ATLL patients and their families without whose support and cooperation this work would not have been possible.

Publisher Copyright:
© 2018 by The American Society of Hematology.

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