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

Gabriela Brumatti, Marika Salmanidis, Chung H. Kok, Rebecca A. Bilardi, Jarrod J. Sandow, Natasha Silke, Kylie Mason, Jolanda Visser, Anissa M. Jabbour, Stefan P. Glaser, Toru Okamoto, Philippe Bouillet, Richard J. D'Andrea, Paul G. Ekert

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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-hydroxy-tamoxifen. 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.

LanguageEnglish
Pages1933-1947
Number of pages15
JournalOncotarget
Volume4
Issue number11
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • Apoptosis
  • Bcl-2
  • HoxA9
  • Leukemia

ASJC Scopus subject areas

  • Oncology

Cite this

Brumatti, Gabriela ; Salmanidis, Marika ; Kok, Chung H. ; Bilardi, Rebecca A. ; Sandow, Jarrod J. ; Silke, Natasha ; Mason, Kylie ; Visser, Jolanda ; Jabbour, Anissa M. ; Glaser, Stefan P. ; Okamoto, Toru ; Bouillet, Philippe ; D'Andrea, Richard J. ; Ekert, Paul G. / HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia. In: Oncotarget. 2013 ; Vol. 4, No. 11. pp. 1933-1947.
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abstract = "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-hydroxy-tamoxifen. 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.",
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Brumatti, G, Salmanidis, M, Kok, CH, Bilardi, RA, Sandow, JJ, Silke, N, Mason, K, Visser, J, Jabbour, AM, Glaser, SP, Okamoto, T, Bouillet, P, D'Andrea, RJ & Ekert, PG 2013, 'HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia', Oncotarget, vol. 4, no. 11, pp. 1933-1947. https://doi.org/10.18632/oncotarget.1306

HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia. / Brumatti, Gabriela; Salmanidis, Marika; Kok, Chung H.; Bilardi, Rebecca A.; Sandow, Jarrod J.; Silke, Natasha; Mason, Kylie; Visser, Jolanda; Jabbour, Anissa M.; Glaser, Stefan P.; Okamoto, Toru; Bouillet, Philippe; D'Andrea, Richard J.; Ekert, Paul G.

In: Oncotarget, Vol. 4, No. 11, 01.01.2013, p. 1933-1947.

Research output: Contribution to journalArticle

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AU - Brumatti, Gabriela

AU - Salmanidis, Marika

AU - Kok, Chung H.

AU - Bilardi, Rebecca A.

AU - Sandow, Jarrod J.

AU - Silke, Natasha

AU - Mason, Kylie

AU - Visser, Jolanda

AU - Jabbour, Anissa M.

AU - Glaser, Stefan P.

AU - Okamoto, Toru

AU - Bouillet, Philippe

AU - D'Andrea, Richard J.

AU - Ekert, Paul G.

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N2 - 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-hydroxy-tamoxifen. 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.

AB - 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-hydroxy-tamoxifen. 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.

KW - Apoptosis

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KW - Leukemia

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