GFP Reporter Cell Line - MOLM13

Dysregulated gene expression is a hallmark of many human cancers. The researchers demonstrated that most subtypes of acute myeloid leukemia (AML) rely on the aberrant assembly of MYB transcriptional co-activator complexes. By employing rapid and selective peptidomimetic interference targeting the binding of CBP/P300 to MYB, while sparing CREB and MLL1, they found that the leukemic activity of MYB is driven by CBP/P300 co-activation of specific transcription factor complexes. These MYB complexes aberrantly associate with LYL1, E2A, C/EBP family members, LMO2, and SATB1, displaying convergent organization across genetically diverse AML subtypes, partially due to inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes results in targeted proteolysis and dynamic redistribution of CBP/P300 to alternative transcription factors like RUNX1, promoting myeloid differentiation and apoptosis. This study reveals that aberrant assembly and sequestration of MYB: CBP/P300 complexes is a unifying mechanism driving oncogenic gene expression in AML, establishing a novel pharmacological reprogramming strategy for therapeutic intervention in diverse leukemias and other cancers characterized by dysregulated gene control.

Figure 1. The researchers highlight the critical role of CBP, but not P300, in the growth and survival of AML cells, and its necessity for susceptibility to peptidomimetic MYB blockade by CRYBMIM. GFP Reporter Cell Line - MOLM13 cells were utilized to assess genetic dependencies and treatment responses through fluorescence-activated cell scanning, demonstrating CBP depletion significantly impacts AML cell growth under CRYBMIM treatment. (Takao S, et al., 2021)