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Impact of loss of BH3-only proteins on the development and treatment of MLL-fusion gene-driven AML in mice.
Bilardi, Rebecca A; Anstee, Natasha S; Glaser, Stefan P; Robati, Mikara; Vandenberg, Cassandra J; Cory, Suzanne.
Afiliación
  • Bilardi RA; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
  • Anstee NS; Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
  • Glaser SP; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
  • Robati M; Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
  • Vandenberg CJ; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
  • Cory S; Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Cell Death Dis ; 7(9): e2351, 2016 09 01.
Article en En | MEDLINE | ID: mdl-27584789
Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model. We tested the sensitivity of MLL-AF9 AMLs of each genotype in vitro to standard chemotherapeutic drugs and to the proteasome inhibitor bortezomib, with or without the BH3 mimetic ABT-737. Loss of Puma and/or Noxa increased resistance to cytarabine, daunorubicin and etoposide, while loss of Bim protected against cytarabine and loss of Bmf had no impact. ABT-737 increased sensitivity to the genotoxic drugs but was not dependent on any BH3-only protein tested. The AML lines were very sensitive to bortezomib and loss of Noxa conveyed significant resistance. In vivo, several MLL-AF9 AMLs responded well to daunorubicin and this response was highly dependent on Puma and Noxa but not Bim. Combination therapy with ABT-737 provided little added benefit at the daunorubicin dose trialed. Bortezomib also extended survival of AML-bearing mice, albeit less than daunorubicin. In summary, our genetic studies reveal the importance of Puma and Noxa for the action of genotoxics currently used to treat MLL-driven AML and suggest that, while addition of ABT-737-like BH3 mimetics might enhance their efficacy, new Noxa-like BH3 mimetics targeting Mcl-1 might have greater potential.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Proteínas de Fusión Oncogénica / Proteínas Proto-Oncogénicas c-bcl-2 / Proteína de la Leucemia Mieloide-Linfoide / Carcinogénesis Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Proteínas de Fusión Oncogénica / Proteínas Proto-Oncogénicas c-bcl-2 / Proteína de la Leucemia Mieloide-Linfoide / Carcinogénesis Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Australia