The PML domain of PML-RARα blocks senescence to promote leukemia

被引：20

作者：

Korf, Katharina ^{[1
]}

Wodrich, Harald ^{[2
]}

Haschke, Alexander ^{[1
]}

Ocampo, Corinne ^{[3
]}

Harder, Lena ^{[1
]}

Gieseke, Friederike ^{[1
]}

Pollmann, Annika ^{[1
]}

Dierck, Kevin ^{[1
]}

Prall, Sebastian ^{[1
]}

Staege, Hannah ^{[6
]}

Ma, Hui ^{[4
]}

Horstmann, Martin A. ^{[1
,7
]}

Evans, Ronald M. ^{[3
,5
]}

Sternsdorf, Thomas ^{[1
]}

机构：

[1] Childrens Canc Ctr Hamburg, Res Inst, D-20251 Hamburg, Germany

[2] Univ Bordeaux Segalen, Unite Mixte Rech 5234, Ctr Natl Rech Sci, F-33076 Bordeaux, France

[3] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA

[4] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[5] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

[6] Leibniz Inst Expt Virol, Heinrich Pette Inst, Dept Gen Virol, D-20251 Hamburg, Germany

[7] Univ Med Ctr Hamburg, Clin Pediat Hematol & Oncol, D-20246 Hamburg, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 33期

关键词：

histone chaperones; leukemogenesis; hematopoiesis; oncogenes; PML nuclear bodies; ACUTE PROMYELOCYTIC LEUKEMIA; RETINOIC ACID; CELLULAR SENESCENCE; PREMATURE SENESCENCE; ONCOGENIC RAS; RECEPTOR; APL; DIFFERENTIATION; TRANSLOCATIONS; ONCOPROTEIN;

D O I：

10.1073/pnas.1412944111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor a (PML-RAR alpha) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RAR alpha (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.

引用

页码：12133 / 12138

页数：6

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