Gata2 as a Crucial Regulator of Stem Cells in Adult Hematopoiesis and Acute Myeloid Leukemia

Stem Cell Reports. 2019 Aug 13;13(2):291-306. doi: 10.1016/j.stemcr.2019.07.005. Epub 2019 Aug 1.

Abstract

Subversion of transcription factor (TF) activity in hematopoietic stem/progenitor cells (HSPCs) leads to the development of therapy-resistant leukemic stem cells (LSCs) that drive fulminant acute myeloid leukemia (AML). Using a conditional mouse model where zinc-finger TF Gata2 was deleted specifically in hematopoietic cells, we show that knockout of Gata2 leads to rapid and complete cell-autonomous loss of adult hematopoietic stem cells. By using short hairpin RNAi to target GATA2, we also identify a requirement for GATA2 in human HSPCs. In Meis1a/Hoxa9-driven AML, deletion of Gata2 impedes maintenance and self-renewal of LSCs. Ablation of Gata2 enforces an LSC-specific program of enhanced apoptosis, exemplified by attenuation of anti-apoptotic factor BCL2, and re-instigation of myeloid differentiation--which is characteristically blocked in AML. Thus, GATA2 acts as a critical regulator of normal and leukemic stem cells and mediates transcriptional networks that may be exploited therapeutically to target key facets of LSC behavior in AML.

Keywords: BCL2; GATA2; acute myeloid leukemia; hematopoiesis; leukemic stem cells; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Self Renewal
  • Disease Models, Animal
  • GATA2 Transcription Factor / antagonists & inhibitors
  • GATA2 Transcription Factor / genetics*
  • GATA2 Transcription Factor / metabolism
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • GATA2 Transcription Factor
  • Gata2 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering