Peptidomimetic blockade of MYB in acute myeloid leukemia

Kavitha Ramaswamy, Lauren Forbes, Gerard Minuesa, Tatyana Gindin, Fiona Brown, Michael G. Kharas, Andrei V. Krivtsov, Scott A. Armstrong, Eric Still, Elisa Stanchina, Birgit Knoechel, Richard Koche and Alex Kentsis ()
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Kavitha Ramaswamy: Sloan Kettering Institute
Lauren Forbes: Sloan Kettering Institute
Gerard Minuesa: Sloan Kettering Institute
Tatyana Gindin: Columbia University Medical Center and New York Presbyterian Hospital
Fiona Brown: Sloan Kettering Institute
Michael G. Kharas: Sloan Kettering Institute
Andrei V. Krivtsov: Sloan Kettering Institute
Scott A. Armstrong: Memorial Sloan Kettering Cancer Center
Eric Still: Sloan Kettering Institute
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Birgit Knoechel: Dana-Farber Cancer Institute
Richard Koche: Sloan Kettering Institute
Alex Kentsis: Sloan Kettering Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02618-6

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DOI: 10.1038/s41467-017-02618-6

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