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

• Published in: eLife Vol. 10
• Main Authors: Takao, Sumiko, Forbes, Lauren, Uni, Masahiro, Cheng, Shuyuan, Pineda, Jose Mario Bello, Tarumoto, Yusuke, Cifani, Paolo, Minuesa, Gerard, Chen, Celine, Kharas, Michael G, Bradley, Robert K, Vakoc, Christopher R, Koche, Richard P, Kentsis, Alex
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 02.02.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acute myeloid leukemia; Apoptosis; Binding sites; Cancer; Cancer Biology; CCAAT/enhancer-binding protein; Cell Line, Tumor; Cloning; CRISPR; Cyclic AMP response element-binding protein; DNA binding proteins; Gene expression; Gene Expression Regulation, Leukemic; Genes; Genetic aspects; Genomes; Health aspects; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Matrix Attachment Region Binding Proteins; Mutation; Myeloid leukemia; Oncogenes; p300-CBP Transcription Factors - genetics; Peptidomimetics; Proteolysis; proteomics; Proto-Oncogene Proteins c-myb - genetics; Proto-Oncogene Proteins c-myb - metabolism; Runx1 protein; Therapeutic targets; Transcription factors; cancer biology; proteomics; human; Leukemia; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.65905

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