Beauchamp EM*,
Leventhal M, Bernard E, Hoppe ER, Todisco G, Creignou M, Gallì A, Castellano CA, McConkey M, Tarun A, Wong W, Schenone M, Stanclift C, Tanenbaum B, Malolepsza E, Nilsson B, Bick AG, Weinstock JS,
Miller M, Niroula A,
Dunford A,
Taylor-Weiner A,
Wood T, Barbera A,
Anand S, Psaty BM, Desai P, Cho MH, Johnson AD, Loos R, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, MacArthur DG, Lek M, Exome Aggregation Consortium, Neuberg DS, Lage K, Carr SA, Hellstrom-Lindberg E, Malcovati L, Papaemmanuil E,
Stewart C,
Getz G, Bradley RK, Jaiswal S
#^, Ebert BL
#^
Blood Cancer Discovery
2
(5)
:500-517
(2021)
Abstract
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.