The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

被引：474

作者：

Harris, William J. ^{[1
]}

Huang, Xu ^{[1
]}

Lynch, James T. ^{[1
]}

Spencer, Gary J. ^{[1
]}

Hitchin, James R. ^{[2
]}

Li, Yaoyong ^{[3
]}

Ciceri, Filippo ^{[1
]}

Blaser, Julian G. ^{[1
]}

Greystoke, Brigit F. ^{[1
]}

Jordan, Allan M. ^{[2
]}

Miller, Crispin J. ^{[3
]}

Ogilvie, Donald J. ^{[2
]}

Somervaille, Tim C. P. ^{[1
]}

机构：

[1] Univ Manchester, Paterson Inst Canc Res, Canc Res UK Leukaemia Biol Lab, Manchester M20 4BX, Lancs, England

[2] Univ Manchester, Paterson Inst Canc Res, Canc Res UK Drug Discovery Unit, Manchester M20 4BX, Lancs, England

[3] Univ Manchester, Paterson Inst Canc Res, Canc Res UK Appl Computat Biol & Bioinformat Grp, Manchester M20 4BX, Lancs, England

来源：

CANCER CELL | 2012年 / 21卷 / 04期

关键词：

ACUTE MYELOID-LEUKEMIA; MIXED-LINEAGE LEUKEMIA; EMBRYONIC STEM; DEVELOPMENTAL REGULATORS; GENE ACTIVATION; LSD1; CHROMATIN; TRANSCRIPTION; COMPLEXES; MAINTENANCE;

D O I：

10.1016/j.ccr.2012.03.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect.

引用

页码：473 / 487

页数：15

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