Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia

被引:516
作者
Schenk, Tino [1 ]
Chen, Weihsu Claire [2 ,3 ]
Goellner, Stefanie [4 ,5 ]
Howell, Louise [1 ]
Jin, Liqing [2 ,3 ]
Hebestreit, Katja [6 ]
Klein, Hans-Ulrich [6 ]
Popescu, Andreea C. [2 ,3 ]
Burnett, Alan [7 ]
Mills, Ken [8 ]
Casero, Robert A., Jr. [9 ]
Marton, Laurence [10 ]
Woster, Patrick [11 ]
Minden, Mark D. [12 ]
Dugas, Martin [6 ]
Wang, Jean C. Y. [2 ,3 ,12 ]
Dick, John E. [2 ,3 ,13 ]
Mueller-Tidow, Carsten [4 ,5 ]
Petrie, Kevin [1 ]
Zelent, Arthur [1 ]
机构
[1] Inst Canc Res, Div Mol Pathol, Sutton, Surrey, England
[2] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada
[3] Ontario Canc Inst, Campbell Family Canc Res Inst, Div Stem Cell & Dev Biol, Toronto, ON M4X 1K9, Canada
[4] Univ Munster, Dept Med Hematol & Oncol, Munster, Germany
[5] Univ Munster, Interdisciplinary Ctr Clin Res IZKF, Munster, Germany
[6] Univ Munster, Inst Med Informat, Munster, Germany
[7] Cardiff Univ, Sch Med, Cardiff, S Glam, Wales
[8] Queens Univ, Sch Med Dent & Biomed Sci, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland
[9] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA
[10] Progen Pharmaceut Inc, Palo Alto, CA USA
[11] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA
[12] Univ Toronto, Dept Med, Toronto, ON, Canada
[13] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
关键词
STEM-CELLS; EXPRESSION; ANALOGS; TARGET; REEXPRESSION; INDUCTION; HIERARCHY; DEATH; RARA; MAP;
D O I
10.1038/nm.2661
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15; 17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID gamma (with interleukin-2 (IL-2) receptor gamma chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
引用
收藏
页码:605 / 611
页数:7
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