RUNX1 and CBFb-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development

Tao Zhen, Yaqiang Cao, Gang Ren, Ling Zhao, R. Katherine Hyde, Guadalupe Lopez, Dechun Feng, Lemlem Alemu, Keji Zhao, P. Paul Liu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFb-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFb-SMMHC–mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11–induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f) with conditional Cbfb-MYH11 knockin mice (Cbfb1/56M). On Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb1/56M mice developed leukemia in 5 months, whereas no leukemia developed in Runx1f/fMx1-CreCbfb1/56M mice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia-initiating cell population induced by Cbfb-MYH11 in the bone marrow, decreased and disappeared in Runx1f/fMx1-CreCbfb1/56M mice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage, and leukemia initiation were differentially expressed between Mx1-CreCbfb1/56M and Runx1f/fMx1-CreCbfb1/56M mice. In addition, with the chromatin immunocleavage sequencing assay, we observed a significant enrichment of RUNX1/ CBFb-SMMHC target genes in Runx1f/fMx1-CreCbfb1/56M cells, especially among downregulated genes, suggesting that RUNX1 and CBFb-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbfb-MYH11–induced leukemogenesis by working together with CBFb-SMMHC to regulate critical genes associated with the generation of a functional AMP population.

Original languageEnglish (US)
Pages (from-to)2373-2385
Number of pages13
JournalBlood
Volume136
Issue number21
DOIs
StatePublished - Nov 19 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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