期刊
BLOOD
卷 136, 期 21, 页码 2373-2385出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020007747
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资金
- Intramural Research Programs of National Human Genome Research Institute
- National Heart, Lung, and Blood Institute, National Institutes of Health
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 CBF beta-SMMHC-mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11-induced leukemia, we crossed conditional Runx1 knockout mice (Runx1(f/f)) with conditional Cbfb-MYH11 knockin mice (Cbfb(+/56M)). On Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb(+/56M) mice developed leukemia in 5 months, whereas no leukemia developed in Runx1(f/f)Mx1-CreCbfb(+/56M) mice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia-initiating cell population induced by Cbf beta-MYH11 in the bone marrow, decreased and disappeared in Runx1(f/f)Mx1-CreCbfb(+/56M) mice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage, and leukemia initiation were differentially expressed between Mx1-CreCbfb(+/56M) and Runx1(f/f)Mx1-CreCbfb(+/56M) mice. In addition, with the chromatin immunocleavage sequencing assay, we observed a significant enrichment of RUNX1/CBF beta-SMMHC target genes in Runx1(f/f)Mx1-CreCbfb(+/56M) cells, especially among downregulated genes, suggesting that RUNX1 and CBF beta-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbf beta-MYH11-induced leukemogenesis by working together with CBF beta-SMMHC to regulate critical genes associated with the generation of a functional AMP population.
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