SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

• Type of Material: Article
• Authors: Patricia Johansson, University of Duisburg-Essen; Ludger Klein-Hitpass, University of Duisburg-Essen; Axel Choidas, Lead Discovery Center GmbH; Peter Habenberger, Lead Discovery Center GmbH; Bijan Mahboubi, Emory University; Baek Kim, Emory University; Anke Bergmann, Christian-Albrechts-University Kiel; Rene Scholtysik, University of Duisburg-Essen; Martina Brauser, University of Duisburg-Essen; Anna Lollies, University of Duisburg-Essen; Reiner Siebert, Christian-Albrechts-University Kiel; Thorsten Zenz, University Hospital Heidelberg; Ulrich Duersen, University of Duisburg-Essen; Ralf Kuepers, University of Duisburg-Essen; Jan Dueig, German Cancer Consortium (DKTK)
• Language: English
• Date: 2018-01-19
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41408-017-0036-5
• Title of Journal or Parent Work: Blood Cancer Journal
• ISSN: 2044-5385
• Volume: 8
• Issue: 1
• Start Page: 11
• End Page: 11
• Grant/Funding Information: P.J. is supported by IFORES.; R.S. is supported through SFB 1074/2 B09*.; This work was supported by a research grant provided from the Dr. Werner Jackstädt-Stiftung, by the Deutsche Krebshilfe (70112112), by National Institutes of Health to B. Kim (GM104198 and AI049781), and by the Deutsche Forschungsgemeinschaft (KU1315/9-2).
• Keywords: Oncology; DNA-DAMAGE; ACUTE LYMPHOBLASTIC-LEUKEMIA; REVERSE-TRANSCRIPTASE; B-CELL; Life Sciences & Biomedicine; SOMATIC MUTATIONS; GENE-EXPRESSION; LYMPHOCYTIC-LEUKEMIA; MOLECULAR SUBTYPES; Science & Technology; FAMILY; CANCER
• Research Categories: Health Sciences, Oncology; Biology, Genetics

Abstract

T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1. SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, and HERC2) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.