CHD7 deficiency delays leukemogenesis in mice induced by CBFB-MYH11
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE102388 | GEO | 2018/08/08
REPOSITORIES: GEO
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Project description:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. However, knockin mice expressing Cbfb-MYH11 (Cbfb+/MYH11) showed defects in primitive hematopoiesis not seen in Cbfb null (Cbfb-/-) embryos indicating that Cbfb-MYH11 has repression independent activities as well. To identify gene expression changes associated with this novel activity, we compared the gene expression profile in the blood cells of Cbfb+/MYH11 and Cbfb-/- embryonic day 12.5 (E12.5) embryos with that of their wildtype littermates. Cbfb-MYH11 chimeras were mated to C57/Bl6 females to generate Cbfb+/MYH11 (Cbfb+/MYH11) and Cbfb+/+ (WT) embryos. Cbfb+/- x Cbfb+/- matings were used to generate Cbfb+/+ (Cbfb+/+) and Cbfb-/- (Cbfb-/-) embryos. Blood from 8-10 E12.5 embryos of the same genotype was pooled, and RNA was isolated, labeled, and hybridized to Affymetrix Genechip mouse microarray (430 2.0) chips. 4 chips were used for both the Cbfb+/MYH11 and littermate control samples. 3 chips were used for the Cbfb-/- samples and littermate control samples.
2010-04-12 | E-GEOD-19194 | biostudies-arrayexpress
Project description:To clarify the role of Gata2 in the development of Cbfb-MYH11 induced leukemia, we generated conditional Cbfb-MYH11 knockin mice with Gata2 heterozygous knockout. Leukemic cells with Gata2 heterozygous knockout gained higher number of genetic mutations and showed more aggressive phenotype in both primary and transplanted recipient mice. We compared gene expression profilings between Gata2+/+ and Gata2+/f leukemic cells with Cbfb-MYH11.
2019-04-26 | GSE130343 | GEO
Project description:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. However, knockin mice expressing Cbfb-MYH11 (Cbfb+/MYH11) showed defects in primitive hematopoiesis not seen in Cbfb null (Cbfb-/-) embryos indicating that Cbfb-MYH11 has repression independent activities as well. To identify gene expression changes associated with this novel activity, we compared the gene expression profile in the blood cells of Cbfb+/MYH11 and Cbfb-/- embryonic day 12.5 (E12.5) embryos with that of their wildtype littermates.
2010-03-31 | GSE19194 | GEO
Project description: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. Previous studies showed that the interaction between CBF?-smooth muscle myosin heavy chain (SMMHC; encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for CBFB-MYH11-induced leukemogenesis. To test this hypothesis, we generated Chd7f/fMx1-CreCbfb+/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The Lin-Sca1-c-Kit+ (LK) population was significantly lower in Chd7f/fMx1-CreCbfb+/56M mice than in Mx1-CreCbfb+/56M mice. In addition, there were fewer 5-bromo-2'-deoxyuridine-positive cells in the LK population in Chd7f/fMx1-CreCbfb+/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb+/56M and Mx1-CreCbfb+/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBF?-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBF?-SMMHC on Csf1r, a RUNX1 target gene. Moreover, RNA sequencing of c-Kit+ cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11-induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11-induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.
| S-EPMC5709785 | biostudies-literature
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
Project description:We searched for genes which are mutated in a manner that is linked with gene mutations involved in DNA de/methylation in AML. We found that recurrent CBFB-MYH11 fusions, which result in the expression of fusion protein comprising core-binding factor β (CBFB) and myosin heavy chain 11 (MYH11), occur mutually exclusively with DNMT3A mutations. The CBFB-MYH11 fusion tumors show DNA hypomethylation patterns similar to cancers with loss-of-function mutation of DNMT3A. Expression of CBFB-MYH11 fusion protein or inhibition of DNMT3A similarly impairs the methylation and expression of target genes of Runt related transcription factor 1 (RUNX1), a functional partner of CBFB. We demonstrate that RUNX1 directly interacts with DNMT3A and that CBFB-MYH11 fusion protein sequesters RUNX1 in the cytoplasm, thereby preventing RUNX1 from interacting with and recruiting DNMT3A to its target genes. Our results identify a novel regulation of DNA methylation and provide a molecular basis how CBFB-MYH11 fusion contributes to leukemogenesis.
2021-04-13 | GSE169682 | GEO
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
Project description:Gata2 deficiency delays leukemogenesis while contributes to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice
| PRJNA535600 | ENA
Project description:Results showed that Chd7 deficiency delay Cbfb-MYH11 induced leukemia, to explore the mechanism, We also performed microarray analysis on c-Kit+ leukemic cells to determine gene expression differences between Mx1-Cre, Cbfb+/56M and Chd7f/f, Mx1-Cre, Cbfb+/56M leukemic cells.
2018-02-14 | GSE103367 | GEO
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. Spleen cells were isolated from leukemic knock-in mice with full length CBFb-SMMHC at 2 months after ENU treatment and 2 leukemic CBFb-SMMHCd179-221 expressing chimeric mice at 3 weeks after birth. For each genotype, we performed two independent experiments with 4 Affymetrix GeneChip 430 chips.
2011-03-29 | E-GEOD-21155 | biostudies-arrayexpress