The Histone Demethylase PHF8 Governs Retinoic Acid Response in Acute Promyelocytic Leukemia

被引：71

作者：

Arteaga, Maria Francisca ^{[1
]}

Mikesch, Jan-Henrik ^{[1
]}

Qiu, Jihui ^{[2
]}

Christensen, Jesper ^{[3
,4
]}

Helin, Kristian ^{[3
,4
,5
]}

Kogan, Scott C. ^{[6
,7
]}

Dong, Shuo ^{[2
]}

So, Chi Wai Eric ^{[1
]}

机构：

[1] Kings Coll London, Dept Haematol Med, Leukaemia & Stem Cell Biol Grp, London SE5 9NU, England

[2] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[3] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark

[4] Univ Copenhagen, Ctr Epigenet, DK-2200 Copenhagen, Denmark

[5] Univ Copenhagen, Danish Stem Cell Ctr Danstem, DK-2200 Copenhagen, Denmark

[6] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

来源：

CANCER CELL | 2013年 / 23卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

LINKED MENTAL-RETARDATION; RAR-ALPHA; HEMATOPOIETIC STEM; FUSION PROTEINS; GENE; NEUROBLASTOMA; TRANSCRIPTION; MUTATIONS; COMPLEX; TARGETS;

D O I：

10.1016/j.ccr.2013.02.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RAR alpha fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.

引用

页码：376 / 389

页数：14

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