TY - JOUR
T1 - RUNX1 and CBFb-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development
AU - Zhen, Tao
AU - Cao, Yaqiang
AU - Ren, Gang
AU - Zhao, Ling
AU - Hyde, R. Katherine
AU - Lopez, Guadalupe
AU - Feng, Dechun
AU - Alemu, Lemlem
AU - Zhao, Keji
AU - Paul Liu, P.
N1 - Funding Information:
The research was supported by the Intramural Research Programs of National Human Genome Research Institute and National Heart, Lung, and Blood Institute, National Institutes of Health.
Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.
PY - 2020/11/19
Y1 - 2020/11/19
N2 - 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.
AB - 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.
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U2 - 10.1182/BLOOD.2020007747
DO - 10.1182/BLOOD.2020007747
M3 - Article
C2 - 32929473
AN - SCOPUS:85096508804
SN - 0006-4971
VL - 136
SP - 2373
EP - 2385
JO - Blood
JF - Blood
IS - 21
ER -