Key Points• A mutation preventing interaction between c-Myb and p300 prevents transformation and leukemia induction by MLL-AF9 and AML1-ETO9a oncogenes.• Identifying agents that block the c-Myb-p300 interaction may be a valuable approach to developing a therapy for acute myeloid leukemia.The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, suggesting that MYB may be a therapeutic target in these diseases. However, realization of this potential requires a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis, and an approach for developing an effective therapeutic. We previously showed that the interaction of c-Myb with the coactivator CBP/p300 is essential for its transforming activity. Here, by using cells from Booreana mice which carry a mutant allele of c-Myb, we show that this interaction is essential for in vitro transformation by the myeloid leukemia oncogenes AML1-ETO, AML1-ETO9a, MLL-ENL, and MLL-AF9. We further show that unlike cells from wild-type mice, Booreana cells transduced with AML1-ETO9a or MLL-AF9 retroviruses fail to generate leukemia upon transplantation into irradiated recipients. Finally, we have begun to explore the molecular mechanisms underlying these observations by gene expression profiling. This identified several genes previously implicated in myeloid leukemogenesis and HSC function as being regulated in a c-Myb-p300-dependent manner. These data highlight the importance of the c-Myb-p300 interaction in myeloid leukemogenesis and suggest disruption of this interaction as a potential therapeutic strategy for acute myeloid leukemia. (Blood. 2014;123(17):2682-2690 IntroductionChromosomal translocations involving transcription factors are commonly associated with the pathogenesis of acute myeloid leukemia (AML).1-3 Two of the most common are the t(8;21)(q22;q22) translocation involving RUNX1(AML1) and RUNX1T1 (ETO) and that involving the KMT2A (MLL) gene on 11q23. The latter can be translocated to many other loci to generate fusions with different partners, although a small subset represents the majority of cases. AMLs with t(8;21)(q22;q22) are generally regarded as having a relatively favorable prognosis, although at least 30% of patients do not survive beyond 5 years postdiagnosis 1 ; in contrast MLL translocations confer a very poor prognosis.

No abstract

No abstract