Impact of loss of BH3-only proteins on the development and treatment of MLL-fusion gene-driven AML in mice
- Author(s)
- Bilardi, RA; Anstee, NS; Glaser, SP; Robati, M; Vandenberg, CJ; Cory, S;
- Details
- Publication Year 2016,Volume 7,Issue #9,Page e2351
- Journal Title
- Cell Death Dis
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- NPG
- Research Division(s)
- Molecular Genetics Of Cancer; Cancer And Haematology
- PubMed ID
- 27584789
- Publisher's Version
- https://doi.org/10.1038/cddis.2016.258
- Open Access at Publisher's Site
http://www.nature.com/cddis/journal/v7/n9/full/cddis2016258a.html- NHMRC Grants
- NHMRC/1016701, NHMRC/1058746,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-10-03 03:38:06
Last Modified: 2016-10-03 03:51:00