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

Blood Cancer Discov. 2021 Sep;2(5):500-517. doi: 10.1158/2643-3230.BCD-20-0224. Epub 2021 Jul 14.

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.

Keywords: clonal hematopoiesis; hematologic malignancies; hematopoietic stem cells; myeloid neoplasia; somatic driver gene discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Clonal Hematopoiesis*
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells
  • Humans
  • Mice
  • Myelodysplastic Syndromes* / genetics
  • RNA Splicing / genetics
  • Transcription Factors / genetics

Substances

  • Transcription Factors
  • Zbtb33 protein, mouse

Grant support