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

Urvi A. Shah, Elaine Y. Chung, Orsolya Giricz, Kith Pradhan, Keisuke Kataoka, Shanisha Gordon-Mitchell, 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 Derman, Adam Binder, Kira Gritsman, Noah Kornblum, Ira Braunschweig, Chirag Bhagat, Jeff Hall, Armin Graber, Lee Ratner, Yanhua Wang, Seishi Ogawa, Amit Verma, B. Hilda Ye and Murali Janakiram

Key points

  • 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.

Abstract

Adult T cell leukemia lymphoma (ATLL) is a rare T cell neoplasm, endemic in the 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 to the Japanese ATLL. To determine genomic differences between these two cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results to 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 TCR/NF-κB pathway genes was significantly lower in our cohort. The most common type of epigenetic mutation is those affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA-seq 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 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 characterized by frequent epigenetic mutations that are targetable preclinically with DNMT inhibitors.

  • Submitted January 2, 2018.
  • Accepted July 25, 2018.