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

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

Research output: Contribution to journal › Article › peer-review

75 Citations (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.

Original language	English
Pages (from-to)	376-89
Number of pages	14
Journal	CANCER CELL
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2013.02.014
Publication status	Published - 18 Mar 2013

Keywords

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

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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.",

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

year = "2013",

month = mar,

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

language = "English",

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journal = "CANCER CELL",

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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

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 - Histones

KW - Histone Demethylases

KW - Humans

KW - Mice, Inbred NOD

KW - Okadaic Acid

KW - Transcription, Genetic

KW - Drug Resistance, Neoplasm

KW - Mice

KW - RNA, Small Interfering

KW - Receptors, Retinoic Acid

KW - Neoplasm Proteins

KW - Tumor Cells, Cultured

KW - Transcription Factors

KW - Phosphorylation

KW - Leukemia, Promyelocytic, Acute

KW - Tretinoin

KW - Mice, SCID

KW - RNA Interference

KW - Signal Transduction

KW - Oncogene Proteins, Fusion

U2 - 10.1016/j.ccr.2013.02.014

DO - 10.1016/j.ccr.2013.02.014

M3 - Article

C2 - 23518351

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

Abstract

Keywords

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