In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

被引：33

作者：

Matsushita, H

Scaglioni, PP

Bhaumik, M

Rego, EM

Cai, LF

Majid, SM

Miyachi, H

Kakizuka, A

Miller, WH

Pandolfi, PP ^{[1
]}

机构：

[1] Cornell Univ, Mem Sloan Kettering Canc Ctr, Dept Pathol, Canc Biol & Genet Program, New York, NY 10021 USA

[2] Cornell Univ, Mem Sloan Kettering Canc Ctr, Weill Grad Sch Med Sci, Dept Med, New York, NY 10021 USA

[3] Tokai Univ, Sch Med, Dept Lab Med, Isehara, Kanagawa 2591193, Japan

[4] Kyoto Univ, Grad Sch Biostudies, Lab Funct Biol, Kyoto 6068501, Japan

[5] McGill Univ, Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2006年 / 203卷 / 04期

关键词：

D O I：

10.1084/jem.20050616

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The promyelocytic leukemia - retinoic acid receptor alpha (PML-RAR alpha) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RAR alpha to inhibit RAR alpha function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1-RAR alpha fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RAR alpha mutants, as well as that of PML-RAR alpha mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RAR alpha did act as a bona fide DN RAR alpha mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RAR alpha mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML-/- and p53(-/-) compound mutants lends support to a model by which the RAR alpha and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

引用

页码：821 / 828

页数：8

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