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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [5C]

ABSTRACT: We demonstrate that CBFb-SMMHCmaintains leukemia viability by inhibiting RUNX1 repression of MYC expression. Upon pharmacologic inhibition of CBF-SMMHC/RUNX1 binding, RUNX1 increases its association with three MYC distal downstream enhancers and represses MYC expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109764 | GEO | 2018/05/02

REPOSITORIES: GEO

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Accelerated leukemogenesis by truncated CBFb-SMMHC defective in high-affinity binding with RUNX1

Project description:Dominant RUNX1 inhibition has been proposed as a common pathway for CBF-leukemia. CBFb-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). We generated knock-in mice expressing CBFb-SMMHC with a HABD deletion, CBFb-SMMHCd179-221. These mice developed leukemia highly efficiently, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. To identify changes in gene expression with the deletion of the HABD, we compared the gene expression profile in leukemia samples from mice expressing CBFb-SMMHCd179-221 with those from mice expressing full length CBFb-SMMHC.

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Accelerated leukemogenesis by truncated CBFb-SMMHC defective in high-affinity binding with RUNX1

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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [5C]

Project description:CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [5C]

| PRJNA431991 | ENA

CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [ChIP-seq]

Project description:We recently reported the discovery of a small molecule inhibitor, AI-10-49 which can specially inhibit the protein-protein interaction between RUNX1 tumor suppressor and CBFβ-SMMHC oncogene. We also demonstrated that AI-10-49 can re-establish the RUNX1 transcriptional program in inv(16) cells and can extend the survival of inv(16) leukemic mice. To identify the epigenetic changes as well as RUNX1 binding associated with AI-10-49, we performed genome wide analysis of H3K27ac histone mark as well as RUNX1 bindings in ME-1 cells [human inv(16) leukemia cell line] treated with AI-10-49.

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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [RNA-seq]

Project description:We recently reported the discovery of a small molecule inhibitor, AI-10-49 which can specially inhibit the protein-protein interaction between RUNX1 tumor suppressor and CBFβ-SMMHC oncogene. We also demonstrated that AI-10-49 can re-establish the RUNX1 transcriptional program in inv(16) cells and can extend the survival of inv(16) leukemic mice. To identify the transcriptional changes associated with AI-10-49, we performed RNA-seq analysis in ME-1 cells [human inv(16) leukemia cell line] treated with AI-10-49.

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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [ATAC-seq]

Project description:We recently reported the discovery of a small molecule inhibitor, AI-10-49 which can specially inhibit the protein-protein interaction between RUNX1 tumor suppressor and CBFβ-SMMHC oncogene. We also demonstrated that AI-10-49 can re-establish the RUNX1 transcriptional program in inv(16) cells and can extend the survival of inv(16) leukemic mice. To identify the changes in chromatin accessibility associated with AI-10-49, we performed ATAC-seq analysis in ME-1 cells [human inv(16) leukemia cell line] treated with AI-10-49.

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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia

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CHD7 deficiency delays leukemogenesis in mice induced by CBFB-MYH11

Project description:CHD7 interacts with CBFb-SMMHC through RUNX1 and modulates their gene expression regulation and is important for CBFB-MYH11 leukemogenesis in the mouse model.

2018-08-08 | GSE102388 | GEO

RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemogenesis

Project description:Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFβ-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 (Cbfb+/56M). Upon Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb+/56M mice developed leukemia in 5 months while no leukemia developed in Runx1f/fMx1-CreCbfb+/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-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 Runx1f/fMx1-CreCbfb+/56M mice. In addition, with chromatin immunocleavage sequencing (ChIC-seq) assay, we observed a significant enrichment of RUNX1/CBFβ-SMMHC target genes in Runx1f/fMx1-CreCbfb+/56M cells, especially among down-regulated genes, suggesting that RUNX1 and CBFβ-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 CBFβ-SMMHC to regulate critical genes associated with the generation of a functional AMP population.

2020-10-06 | GSE152573 | GEO

CBFβ-SMMHC affects genome-wide Polycomb Repressive Complex 1 activity in Acute Myeloid Leukemia

Project description:Polycomb activity is frequently altered in acute leukaemia through mutation or deletion of Polycomb Repressive Complex (PRC) components. Alterations in PRC-interacting factors such as the Core Binding Factor (CBF) complex should also affect leukemia biology, even if PRC composition is normal. We report that the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein physically interacts with the PRC1 complex, and that these factors co-localize across the AML genome in a PRC2-independent manner. Depletion of CBFβ-SMMHC caused increases in genome-wide PRC1 binding and an altered association between PRC1 and RUNX1. Overall, PRC1 was more likely to be associated with active genes. CBFβ-SMMHC depletion had variable transcriptional effects, including significant reductions in expression of PRC1-bound ribosomal loci. Our results expand on the recently reported localized effect of CBFβ-SMMHC on RUNX1-mediated recruitment of PRC1 at MYC enhancer elements, providing evidence that the oncoprotein diversely affects Polycomb recruitment and transcriptional regulation across the entire AML genome.

2020-01-22 | GSE128771 | GEO

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