Peptidomimetic blockade of MYB in acute myeloid leukemia Journal Article

Authors: Ramaswamy, K.; Forbes, L.; Minuesa, G.; Gindin, T.; Brown, F.; Kharas, M. G.; Krivtsov, A. V.; Armstrong, S. A.; Still, E.; de Stanchina, E.; Knoechel, B.; Koche, R.; Kentsis, A.
Article Title: Peptidomimetic blockade of MYB in acute myeloid leukemia
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. © 2017 The Author(s).
Keywords: cancer survival; controlled study; unclassified drug; human cell; cancer growth; drug efficacy; nonhuman; treatment duration; animal cell; mouse; animal tissue; cell viability; mus; protein bcl 2; apoptosis; gene expression; protein assembly; molecular dynamics; animal experiment; animal model; protein; in vivo study; antineoplastic activity; drug structure; in vitro study; inhibitor; drug design; gene expression regulation; nucleotide sequence; myc protein; molecular analysis; single drug dose; binding site; down regulation; drug blood level; immune deficiency; double blind procedure; mitochondrion; drug protein binding; concentration response; protein inhibitor; enhancer region; cell; multiprotein complex; e1a associated p300 protein; chemical binding; complexity; mixed lineage leukemia protein; acute myeloid leukemia; antileukemic agent; activation energy; protein myb; cyclic amp responsive element binding protein binding protein; ectopic expression; cancer; human; female; article; acute myeloid leukemia cell line; mybmim peptide; peptidomimetic agent
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-01-09
Start Page: 110
Language: English
DOI: 10.1038/s41467-017-02618-6
PROVIDER: scopus
PMCID: PMC5760651
PUBMED: 29317678
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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