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

• DOI: 10.7554/elife.65905
• Publication Date: 2021-02-02T15:54:19Z
• Authors: Sumiko Takao; Lauren Forbes; Masahiro Uni; Shuyuan Cheng; Jose Mario Bello ...; Yusuke Tarumoto; Paolo Cifani; Gerard Minuesa; Celine Chen; Michael G Kharas; Robert K Bradley; Christopher R Vakoc; Richard P Koche; Alex Kentsis
• Keywords: MYB; CREB-binding protein; RUNX1; P300-CBP Transcription Factors

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with binding CBP/P300 MYB, but not CREB or MLL1, find leukemic functions are mediated by co-activation a distinct set transcription factor complexes. These complexes assemble aberrantly LYL1, E2A, C/EBP family members, LMO2, SATB1. They organized convergently genetically diverse AML at least part associated inappropriate co-expression. Peptidomimetic remodeling oncogenic is accompanied specific proteolysis dynamic redistribution alternative factors such as RUNX1 induce differentiation apoptosis. Thus, sequestration MYB:CBP/P300 provide unifying mechanism AML. This work establishes compelling strategy for their pharmacologic reprogramming therapeutic targeting leukemias possibly other cancers caused dysregulated control.