Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11.
Core-binding factor beta (CBFbeta) and CBFalpha2 form a heterodimeric transcription factor that plays an important role in hematopoiesis. The genes encoding either CBFbeta or CBFalpha2 are involved in chromosomal rearrangements in more than 30% of cases of acute myeloid leukemia (AML), suggesting that CBFbeta and CBFalpha2 play important roles in leukemogenesis. Inv(16)(p13;q22) is found in almost all cases of AML M4Eo and results in the fusion of CBFB with MYH11, the gene encoding smooth muscle myosin heavy chain. Mouse embryos heterozygous for a Cbfb-MYH11 knock-in gene lack definitive hematopoiesis, a phenotype shared by Cbfb(-/-) embryos. In this study we generated a Cbfb-GFP knock-in mouse model to characterize the normal expression pattern of Cbfbeta in hematopoietic cells. In midgestation embryos, Cbfbeta was expressed in populations enriched for hematopoietic stem cells and progenitors. This population of stem cells and progenitors was not present in mouse embryos heterozygous for the Cbfb-MYH11 knock-in gene. Together, these data suggest that Cbfb-MYH11 blocks embryonic hematopoiesis at the stem-progenitor cell level and that Cbfb is essential for the generation of hematopoietic stem and progenitor cells. In adult mice, Cbfbeta was expressed in stem and progenitor cells, as well as mature myeloid and lymphoid cells. Although it was expressed in erythroid progenitors, Cbfbeta was not expressed during the terminal stages of erythropoiesis. Our data indicate that Cbfb is required for myeloid and lymphoid differentiation; but does not play a critical role in erythroid differentiation.
Kundu
Mondira
M
Genetics and Molecular Biology Branch and Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Chen
Amy
A
Anderson
Stacie
S
Kirby
Martha
M
Xu
LiPing
L
Castilla
Lucio H
LH
Bodine
David
D
Liu
Pu Paul
PP
D000818:Animals; D003114:Colony-Forming Units Assay; D050658:Core Binding Factor beta Subunit; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005822:Genetic Vectors; D005838:Genotype; D049452:Green Fluorescent Proteins; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D018995:Myosin Heavy Chains / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics*
C493692:CBFB protein, human; C493693:Cbfb protein, mouse; D050658:Core Binding Factor beta Subunit; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D018995:Myosin Heavy Chains