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

Peptidomimetic blockade of MYB in acute myeloid leukemia.

Author information

1
Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, 10065, USA.
2
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
3
Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA.
4
Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, 10065, USA.
5
Center for Epigenetics Research, Sloan Kettering Institute, New York, NY, 10065, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
7
Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
8
Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, 10065, USA. kentsisresearchgroup@gmail.com.
9
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. kentsisresearchgroup@gmail.com.
10
Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA. kentsisresearchgroup@gmail.com.

Abstract

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.

PMID:
29317678
PMCID:
PMC5760651
DOI:
10.1038/s41467-017-02618-6
[Indexed for MEDLINE]
Free PMC Article

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