Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia

被引：205

作者：

Kuhn, Michael W. M. ^{[1
,2
]}

Song, Evelyn ^{[1
]}

Feng, Zhaohui ^{[1
]}

Sinha, Amit ^{[1
]}

Chen, Chun-Wei ^{[1
]}

Deshpande, Aniruddha J. ^{[1
]}

Cusan, Monica ^{[1
]}

Farnoud, Noushin ^{[1
]}

Mupo, Annalisa ^{[3
]}

Grove, Carolyn ^{[4
,5
]}

Koche, Richard ^{[1
]}

Bradner, James E. ^{[6
]}

de Stanchina, Elisa ^{[7
]}

Vassiliou, George S. ^{[3
]}

Hoshii, Takayuki ^{[1
]}

Armstrong, Scott A. ^{[1
,8
,9
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA

[2] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med 3, Mainz, Germany

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] PathWest Sir Charles Gairdner Hosp, Dept Haematol, Nedlands, WA, Australia

[5] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA, Australia

[6] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[7] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Facil, 1275 York Ave, New York, NY 10021 USA

[8] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA USA

[9] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA

来源：

CANCER DISCOVERY | 2016年 / 6卷 / 10期

关键词：

ACUTE MYELOID-LEUKEMIA; MLL-REARRANGED LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; TUMOR-SUPPRESSOR MENIN; CYTOPLASMIC NUCLEOPHOSMIN; PROGNOSTIC-SIGNIFICANCE; H3K79; METHYLATION; NORMAL KARYOTYPE; DOT1L INHIBITOR; FUNCTIONAL-ROLE;

D O I：

10.1158/2159-8290.CD-16-0237

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (NPM1(mut)) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1(mut) AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1(mut) 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 NPM1(mut) 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 NPM1(mut) leukemia. SIGNIFICANCE: MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1(mut) AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. (C) 2016 AACR.

引用

页码：1166 / 1181

页数：16

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