Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia Journal Article

   

Authors:	Kühn, M. W. M.; Song, E.; Feng, Z.; Sinha, A.; Chen, C. W.; Deshpande, A. J.; Cusan, M.; Farnoud, N.; Mupo, A.; Grove, C.; Koche, R.; Bradner, J. E.; de Stanchina, E.; Vassiliou, G. S.; Hoshii, T.; Armstrong, S. A.
Article Title:	Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia
Abstract:	Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin–MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1mut AML. Combined pharmacologic inhibition of menin–MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. SIGNIFICANCE: MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. © 2016 American Association for Cancer Research.
Journal Title:	Cancer Discovery
Volume:	6
Issue:	10
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2016-10-01
Start Page:	1166
End Page:	1181
Language:	English
DOI:	10.1158/2159-8290.cd-16-0237
PROVIDER:	scopus
PUBMED:	27535106
PMCID:	PMC5584808
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-84994104392&partnerID=40&md5=bcbcf730b8195159905543c8e8e35112
Notes:	Article -- Export Date: 6 December 2016 -- Source: Scopus

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