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 F. 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 journalArticle

17 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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Shah, U. A., Chung, E. Y., Giricz, O., Pradhan, K., Kataoka, K., Gordon-Mitchel, S., Bhagat, T. D., Mai, Y., Wei, Y., Ishida, E., Choudhary, G. S., Joseph, A., Rice, R., Gitego, N., Parrish, C., Bartenstein, M., Goel, S., Mantzaris, I., Shastri, A., ... Janakiram, M. (2018). North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies. Blood, 132(14), 1507-1518. https://doi.org/10.1182/blood-2018-01-824607