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

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

PROVIDER: PRJNA528866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15680484_1.fastq.gz	Fastqsanger.gz
	SRR15680484_2.fastq.gz	Fastqsanger.gz
	SRR15680485_1.fastq.gz	Fastqsanger.gz
	SRR15680485_2.fastq.gz	Fastqsanger.gz
	SRR8777090_1.fastq.gz	Fastqsanger.gz

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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

CBFβ-SMMHC-driven leukemogenesis requires enhanced RUNX1-DNA binding affinity in mice

Project description:The leukemia fusion gene CBFB-MYH11 requires RUNX1 for leukemogenesis, but the underlying mechanism is unclear. By in vitro studies, we found that CBFβ-SMMHC, the chimeric protein encoded by CBFB-MYH11, could enhance the binding affinity between RUNX1 and its target DNA. Increased RUNX1-DNA binding was also observed in myeloid progenitor cells from mice expressing CBFβ-SMMHC. Moreover, only CBFβ-SMMHC variants able to enhance the DNA binding affinity by RUNX1 could induce leukemia in mouse models. Significant transcriptomic changes, affecting genes associated with inflammatory response and target genes of CBFA2T3, were observed in mice expressing leukemogenic CBFβ-SMMHC variants. Finally, we show that CBFβ-SMMHC could not induce leukemia in mice with a Runx1-R188Q mutation, which reduces RUNX1 DNA binding but not affecting its interaction with CBFβ-SMMHC or its sequestration to cytoplasm by CBFβ-SMMHC. Our data suggest that enhancing RUNX1-target DNA binding affinity is an important mechanism of leukemogenesis by CBFβ-SMMHC.

2025-06-23 | GSE285824 | GEO

The C-terminal multimerization domain is essential for leukemia development by CBFβ-SMMHC

Project description:The recurrent chromosome 16 inversion in acute myeloid leukemia generates a fusion gene between CBFB and MYH11, which in turn encodes a chimeric protein CBFβ-SMMHC (core binding factor β-smooth muscle myosin heavy chain). We previously demonstrated that CBFβ-SMMHC needs its C terminal domains for leukemogenesis. In this study, we generated a new Cbfb-MYH11 knock-in mouse model to dissect the role of the multimerization domain at the C terminus of CBFβ-SMMHC. Specifically, we mutated six amino acids in the helices D and E (mDE) of the assembly competent domain, which is important for SMMHC multimerization. We found that the embryos with the mDE mutation (Cbfb+/mDE) did not develop hematopoietic defects seen in embryos with full-length CBFβ-SMMHC (Cbfb+/MYH11). More importantly leukemia development was abolished in the adult Cbfb+/mDE mice even after mutagenesis treatment. In addition, gene expression profile of the hematopoietic cells from the Cbfb+/mDE mice was more similar to that of Cbfb+/+ mice than the Cbfb+/MYH11 mice. Our data suggest that the C terminal multimerization domain is required for the defects in primitive and definitive hematopoiesis caused by CBFβ-SMMHC, and it is also essential for leukemogenesis caused by CBFβ-SMMHC.

2018-06-15 | GSE100061 | 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-driven leukemogenesis requires enhanced RUNX1-DNA binding affinity in mice

Project description:CBFβ-SMMHC-driven leukemogenesis requires enhanced RUNX1-DNA binding affinity in mice

| PRJNA1206157 | ENA

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

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

| PRJNA639776 | ENA

DDX5-deficiency affects cell fate decisions by regulating lineage specific genes and polycomb repressive complexes

Project description:DDX5-deficiency affects cell fate decisions by regulating lineage specific genes and polycomb repressive complexes

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LATS2 regulates repressive epigenetic integrity via regulation of Polycomb repressive complex 2

Project description:LATS2 regulates repressive epigenetic integrity via regulation of Polycomb repressive complex 2

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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.

2018-05-02 | GSE101788 | GEO

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.

2018-05-02 | GSE101790 | GEO

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