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ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing


Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

Type Journal
ISBN 2643-3249 (Electronic) 2643-3230 (Linking)
Authors Beauchamp, E. M.; Leventhal, M.; Bernard, E.; Hoppe, E. R.; Todisco, G.; Creignou, M.; Galli, A.; Castellano, C. A.; McConkey, M.; Tarun, A.; Wong, W.; Schenone, M.; Stanclift, C.; Tanenbaum, B.; Malolepsza, E.; Nilsson, B.; Bick, A. G.; Weinstock, J. S.; Miller, M.; Niroula, A.; Dunford, A.; Taylor-Weiner, A.; Wood, T.; Barbera, A.; Anand, S.; Psaty, B. M.; Desai, P.; Cho, M. H.; Johnson, A. D.; Loos, R.; Consortium, Nhlbi Trans-Omics for Precision Medicine; MacArthur, D. G.; Lek, M.; Exome Aggregation, Consortium; Neuberg, D. S.; Lage, K.; Carr, S. A.; Hellstrom-Lindberg, E.; Malcovati, L.; Papaemmanuil, E.; Stewart, C.; Getz, G.; Bradley, R. K.; Jaiswal, S.; Ebert, B. L.
Responsible Garvan Author Prof Daniel MacArthur
Publisher Name Blood Cancer Discovery
Published Date 2021-09-30
Published Volume 2
Published Issue 5
Published Pages 500-517
Status Published in-print
DOI 10.1158/2643-3230.BCD-20-0224
URL link to publisher's version