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

Maria Francisca Arteaga; Jan-Henrik Mikesch; Jihui Qiu; Jesper Aagaard Christensen; Kristian Helin; Scott C Kogan; Shuo Dong; Chi Wai Eric So

doi:10.1016/j.ccr.2013.02.014

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

Maria Francisca Arteaga, Jan-Henrik Mikesch, Jihui Qiu, Jesper Aagaard Christensen, Kristian Helin, Scott C Kogan, Shuo Dong, Chi Wai Eric So

DanStem

63 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	23
Udgave nummer	3
Sider (fra-til)	376-89
Antal sider	14
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccr.2013.02.014
Status	Udgivet - 18 mar. 2013

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10.1016/j.ccr.2013.02.014

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title = "The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia",

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.",

keywords = "Animals, Drug Resistance, Neoplasm, Histone Demethylases, Histones, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins, Okadaic Acid, Oncogene Proteins, Fusion, Phosphorylation, RNA Interference, RNA, Small Interfering, Receptors, Retinoic Acid, Signal Transduction, Transcription Factors, Transcription, Genetic, Tretinoin, Tumor Cells, Cultured",

author = "Arteaga, {Maria Francisca} and Jan-Henrik Mikesch and Jihui Qiu and Christensen, {Jesper Aagaard} and Kristian Helin and Kogan, {Scott C} and Shuo Dong and So, {Chi Wai Eric}",

year = "2013",

month = mar,

day = "18",

doi = "10.1016/j.ccr.2013.02.014",

language = "English",

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journal = "Cancer Cell",

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TY - JOUR

T1 - The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia

AU - Arteaga, Maria Francisca

AU - Mikesch, Jan-Henrik

AU - Qiu, Jihui

AU - Christensen, Jesper Aagaard

AU - Helin, Kristian

AU - Kogan, Scott C

AU - Dong, Shuo

AU - So, Chi Wai Eric

PY - 2013/3/18

Y1 - 2013/3/18

N2 - 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.

AB - 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.

KW - Animals

KW - Drug Resistance, Neoplasm

KW - Histone Demethylases

KW - Histones

KW - Humans

KW - Leukemia, Promyelocytic, Acute

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Neoplasm Proteins

KW - Okadaic Acid

KW - Oncogene Proteins, Fusion

KW - Phosphorylation

KW - RNA Interference

KW - RNA, Small Interfering

KW - Receptors, Retinoic Acid

KW - Signal Transduction

KW - Transcription Factors

KW - Transcription, Genetic

KW - Tretinoin

KW - Tumor Cells, Cultured

U2 - 10.1016/j.ccr.2013.02.014

DO - 10.1016/j.ccr.2013.02.014

M3 - Journal article

C2 - 23518351

SN - 1535-6108

VL - 23

SP - 376

EP - 389

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

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