Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

Abstract

@KentsisResearch 2 HIGHLIGHTS • Cell-penetrant peptidomimetic inhibitor selectively blocks oncogenic MYB:CBP/P300 activity in diverse leukemias but not normal blood cells • MYB assembles aberrant transcription factor complexes in AML required for programming leukemic gene expression • CBP/P300 sequestration contributes to MYB-dependent leukemogenic gene expression and chromatin organization SUMMARYDysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. We propose that convergently organized transcription factor complexes in AML cells control oncogenic gene expression programs. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and possibly other human cancers caused by dysregulated gene control.3

Immature acute leukaemias: lessons from the haematopoietic roadmap

“…While T/Myeloid MPALs showed higher levels of methylation in general, T-lymphoid ontogeny was reflected by hypomethylation of T-receptor signalling factor genes. Also in line with these concepts of global epigenetic dysregulation, recent intriguing data [97] have suggested that some cases of AML have epigenomic landscape changes reminiscent of the MYB regulatory complex reorganisation that is also found in T-ALL [98,99].…”