Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

被引：182

作者：

Chen, Chong ^{[1
]}

Liu, Yu ^{[1
]}

Lu, Chao ^{[1
,2
]}

Cross, Justin R. ^{[3
]}

Morris, John P. ^{[1
]}

Shroff, Aditya S. ^{[1
]}

Ward, Patrick S. ^{[1
,2
]}

Bradner, James E. ^{[4
]}

Thompson, Craig ^{[1
]}

Lowe, Scott W. ^{[1
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Univ Penn, Perelman Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA

[3] Mem Sloan Kettering Canc Ctr, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA

[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[5] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

GENES & DEVELOPMENT | 2013年 / 27卷 / 18期

关键词：

AML; Brd4; inhibition; IDH mutants; targeted therapy; tumor maintenance; RECURRING MUTATIONS; FLT3; 2-HYDROXYGLUTARATE; DIFFERENTIATION; CELLS; PROLIFERATION; PROGENITORS; SUFFICIENT; RAS;

D O I：

10.1101/gad.226613.113

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.

引用

页码：1974 / 1985

页数：12

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