Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA126601 | ENA |
REPOSITORIES: ENA
Similar Datasets
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.
2011-03-29 | GSE21155 | 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
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
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: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: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.
2018-05-02 | GSE109764 | GEO
Project description:The C-terminus of CBFß-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-mulimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFß-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFß-SMMHC (CBFß-SMMHCΔC95). Embryos with a single copy of CBFß-SMMHCDC95 were viable and showed no defects in hematopoiesis, while embryos homozygous for the CBFß-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFß-SMMHCΔC95. To identify gene expression changes induced by CBFß-SMMHCDC95, we compared the gene expression profile in the blood cells of Cbfb+/+, Cbfb+/ΔC95, and CbfbΔC95/ΔC95 embryonic day 12.5 (E12.5) mice. Cbfb+/ΔC95 were mated together to generate Cbfb+/+, Cbfb+/ΔC95, and CbfbΔC95/ΔC95 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. 3 chips were used for each genotype.
2013-02-19 | E-GEOD-42238 | biostudies-arrayexpress
Project description:The C-terminus of CBFß-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-mulimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFß-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFß-SMMHC (CBFß-SMMHCΔC95). Embryos with a single copy of CBFß-SMMHCDC95 were viable and showed no defects in hematopoiesis, while embryos homozygous for the CBFß-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFß-SMMHCΔC95. To identify gene expression changes induced by CBFß-SMMHCDC95, we compared the gene expression profile in the blood cells of Cbfb+/+, Cbfb+/ΔC95, and CbfbΔC95/ΔC95 embryonic day 12.5 (E12.5) mice.
2013-02-19 | GSE42238 | 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: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