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PMID: 23518351 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia.

Cancer cell ·Vol. 23 ·No. 3 ·2013-03-18 ·Pages 376-89

Arteaga MF, Mikesch JH, Qiu J, Christensen J, Helin K, Kogan SC, Dong S, So CW

Abstract

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 RARα 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.

MeSH Terms
Animals Drug Resistance, Neoplasm Histone Demethylases/genetics,metabolism Histones Humans Leukemia, Promyelocytic, Acute/drug therapy,metabolism Mice Mice, Inbred NOD Mice, SCID Neoplasm Proteins/metabolism Okadaic Acid/pharmacology Oncogene Proteins, Fusion/metabolism Phosphorylation RNA Interference RNA, Small Interfering Receptors, Retinoic Acid/genetics,metabolism Retinoic Acid Receptor alpha Signal Transduction Transcription Factors/genetics,metabolism Transcription, Genetic Tretinoin/pharmacology Tumor Cells, Cultured
Chemicals
Histones Neoplasm Proteins Oncogene Proteins, Fusion RARA protein, human RNA, Small Interfering Rara protein, mouse Receptors, Retinoic Acid Retinoic Acid Receptor alpha Transcription Factors Okadaic Acid Tretinoin Histone Demethylases PHF8 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Arteaga Maria Francisca
Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Denmark Hill, London SE5 9NU, UK.
Mikesch Jan-Henrik
Qiu Jihui
Christensen Jesper
Helin Kristian
Kogan Scott C
Dong Shuo
So Chi Wai Eric
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2013.02.014
Published
2013-03-18
Pages
376-89
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC6812572
Subset
IM
Grants
NCI NIH HHS · R01 CA095274 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2013.02.014 PMC Full Text View journal details
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