HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia

被引：42

作者：

Brumatti, Gabriela ^{[1
,2
]}

Salmanidis, Marika ^{[1
,2
,5
]}

Kok, Chung H. ^{[7
,8
,9
,10
]}

Bilardi, Rebecca A. ^{[1
,2
]}

Sandow, Jarrod J. ^{[1
,2
]}

Silke, Natasha ^{[1
,2
]}

Mason, Kylie ^{[1
,6
]}

Visser, Jolanda ^{[1
,11
]}

Jabbour, Anissa M. ^{[1
,2
]}

Glaser, Stefan P. ^{[1
,2
]}

Okamoto, Toru ^{[12
]}

Bouillet, Philippe ^{[1
,2
]}

D'Andrea, Richard J. ^{[7
,8
,9
,10
]}

Ekert, Paul G. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

[3] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[4] Royal Childrens Hosp, Childrens Canc Ctr, Parkville, Vic 3052, Australia

[5] Univ Melbourne, Dept Pediat, Parkville, Vic 3052, Australia

[6] Univ Melbourne, Dept Med, Parkville, Vic 3052, Australia

[7] SA Pathol, Dept Hematol, Adelaide, SA, Australia

[8] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia

[9] Queen Elizabeth Hosp, Dept Hematol & Oncol, Woodville, SA 5011, Australia

[10] Univ Adelaide, Discipline Med, Adelaide, SA 5005, Australia

[11] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands

[12] Osaka Univ, Microbial Dis Res Inst, Dept Mol Virol, Suita, Osaka, Japan

来源：

ONCOTARGET | 2013年 / 4卷 / 11期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

HoxA9; Bcl-2; Leukemia; apoptosis; ANTI-APOPTOTIC MCL-1; STEM-CELLS; HOMEODOMAIN PROTEINS; GENE; TRANSFORMATION; DETERMINES; MLL-AF9; PBX; AML; DNA;

D O I：

10.18632/oncotarget.1306

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxytamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro. Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia.

引用

页码：1933 / 1947

页数：15

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