Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice.
CBFβ-SMMHC (core-binding factor β-smooth muscle myosin heavy chain), the fusion protein generated by the chromosome 16 inversion fusion gene, CBFB-MYH11, is known to initiate leukemogenesis. However, the mechanism through which CBFβ-SMMHC contributes to leukemia development is not well understood. Previously, it was proposed that CBFβ-SMMHC acts by dominantly repressing the transcription factor RUNX1 (Runt-related protein 1), but we recently showed that CBFβ-SMMHC has activities that are independent of RUNX1 repression. In addition, we showed that a modified CBFβ-SMMHC with decreased RUNX1-binding activity accelerates leukemogenesis. These results raise questions about the importance of RUNX1 in leukemogenesis by CBFβ-SMMHC. To test this, we generated mice expressing Cbfb-MYH11 in a Runx1-deficient background, resulting from either homozygous Runx1-null alleles (Runx1(-/-)) or a single dominant-negative Runx1 allele (Runx1(+/lz)). We found that loss of Runx1 activity rescued the differentiation defects induced by Cbfb-MYH11 during primitive hematopoiesis. During definitive hematopoiesis, RUNX1 loss also significantly reduced the proliferation and differentiation defects induced by Cbfb-MYH11. Importantly, Cbfb-MYH11-induced leukemia had much longer latency in Runx1(+/lz) mice than in Runx1-sufficient mice. These data indicate that Runx1 activity is critical for Cbfb-MYH11-induced hematopoietic defects and leukemogenesis.
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Hyde
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Zhao
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Alemu
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Liu
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D050658:Core Binding Factor beta Subunit / Q000502:physiology*; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007938:Leukemia / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018995:Myosin Heavy Chains / Q000502:physiology*
C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C493726:Runx1 protein, mouse; C573943:myosin 11, mouse; D018995:Myosin Heavy Chains