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Ref Type Journal Article
PMID (27535106)
Authors Kühn MW, Song E, Feng Z, Sinha A, Chen CW, Deshpande AJ, Cusan M, Farnoud N, Mupo A, Grove C, Koche R, Bradner JE, de Stanchina E, Vassiliou GS, Hoshii T, Armstrong SA
Title Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia.
Journal Cancer discovery
Vol 6
Issue 10
Date 2016 10
URL
Abstract Text 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.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. Cancer Discov; 6(10); 1166-81. ©2016 AACR.See related commentary by Hourigan and Aplan, p. 1087This article is highlighted in the In This Issue feature, p. 1069.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MI-503 MI-503 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
EPZ004777 EPZ4777|EPZ-004777|EPZ 004777 DOT1L Inhibitor 3 EPZ004777 is a small molecule that inhibits DOT1L, which results in decreased histone H3 lysine 79 dimethylation, and potentially leads to decreased tumor cell proliferation (PMID: 21741596, PMID: 27535106, PMID: 31888761).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NPM1 mutant leukemia predicted - sensitive EPZ004777 Preclinical Actionable In preclinical study, treatment with EPZ004777 resulted in reduced proliferation and increased differentiation of murine leukemia cells expressing an NPM1 mutation, and improved survival in NPM1-mutant murine leukemia models (PMID: 27535106). 27535106
FLT3 exon 14 ins NPM1 mut leukemia predicted - sensitive MI-503 Preclinical Actionable In a preclinical study, MI-503 inhibited growth of murine leukemia cells expressing an NPM1 mutation and FLT3 internal tandem duplication in culture, and improved survival in mouse models (PMID: 27535106). 27535106
NPM1 mutant acute myeloid leukemia predicted - sensitive EPZ004777 Preclinical - Patient cell culture Actionable In a preclinical study, EPZ004777 decreased HOX gene expression, and reduced proliferation and increased differentiation of a human acute myeloid leukemia (AML) cell line and primary AML samples harboring NPM1 mutations in culture (PMID: 27535106). 27535106
NPM1 mutant acute myeloid leukemia predicted - sensitive MI-503 Preclinical - Cell line xenograft Actionable In a preclinical study, MI-503 inhibited growth of an acute myeloid leukemia cell line and primary AML samples harboring NPM1 mutations in culture, and reduced tumor burden and improved survival in an NPM1-mutant AML cell line xenograft model (PMID: 27535106). 27535106
FLT3 exon 14 ins NPM1 mut leukemia predicted - sensitive EPZ004777 Preclinical Actionable In a preclinical study, EPZ004777 inhibited growth and induced differentiation of murine leukemia cells expressing an NPM1 mutation and FLT3 internal tandem duplication in culture, and improved survival in mouse models (PMID: 27535106). 27535106