Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness

Elizabeth L. Ostrander, Ashley C. Kramer, Cates Mallaney, Hamza Celik, Won Kyun Koh, Jake Fairchild, Emily Haussler, Christine R.C. Zhang, Grant A. Challen

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The DNA methylation regulators DNMT3A and TET2 are recurrently mutated in hematological disorders. Despite possessing antagonistic biochemical activities, loss-of-function murine models show overlapping phenotypes in terms of increased hematopoietic stem cell (HSC) fitness. Here, we directly compared the effects of these mutations on hematopoietic progenitor function and disease initiation. In contrast to Dnmt3a-null HSCs, which possess limitless self-renewal in vivo, Tet2-null HSCs unexpectedly exhaust at the same rate as control HSCs in serial transplantation assays despite an initial increase in self-renewal. Moreover, loss of Tet2 more acutely sensitizes hematopoietic cells to the addition of a common co-operating mutation (Flt3ITD) than loss of Dnmt3a, which is associated with a more rapid expansion of committed progenitor cells. The effect of Tet2 mutation manifests more profound myeloid lineage skewing in committed hematopoietic progenitor cells rather than long-term HSCs. Molecular characterization revealed divergent transcriptomes and chromatin accessibility underlying these functional differences.

Original languageEnglish
Pages (from-to)551-560
Number of pages10
JournalStem Cell Reports
Volume14
Issue number4
DOIs
StatePublished - Apr 14 2020

Keywords

  • DNMT3A
  • TET2
  • clonal hematopoiesis
  • hematopoietic stem cell

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