Peptidomimetic blockade of MYB in acute myeloid leukemia

Nat Commun. 2018 Jan 9;9(1):110. doi: 10.1038/s41467-017-02618-6.


Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Binding Sites / physiology
  • Biomimetic Materials / pharmacology*
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Female
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Molecular Dynamics Simulation
  • Peptidomimetics / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-myb / biosynthesis
  • Proto-Oncogene Proteins c-myb / genetics*
  • Transcriptional Activation / genetics*
  • Xenograft Model Antitumor Assays / methods
  • p300-CBP Transcription Factors / biosynthesis
  • p300-CBP Transcription Factors / genetics*


  • Peptidomimetics
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myb
  • Bcl2 protein, mouse
  • p300-CBP Transcription Factors