Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice.

ABSTRACT: CBF?-SMMHC (core-binding factor ?-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 CBF?-SMMHC contributes to leukemia development is not well understood. Previously, it was proposed that CBF?-SMMHC acts by dominantly repressing the transcription factor RUNX1 (Runt-related protein 1), but we recently showed that CBF?-SMMHC has activities that are independent of RUNX1 repression. In addition, we showed that a modified CBF?-SMMHC with decreased RUNX1-binding activity accelerates leukemogenesis. These results raise questions about the importance of RUNX1 in leukemogenesis by CBF?-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.

SUBMITTER: Hyde RK 

PROVIDER: S-EPMC4526349 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature