title: Impact of loss of BH3-only proteins on the development and treatment of MLL-fusion gene-driven AML in mice.
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.
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Rebecca A
authors: RA
authors: Bilardi
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Natasha S
authors: NS
authors: Anstee
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Stefan P
authors: SP
authors: Glaser
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
authors: Mikara
authors: M
authors: Robati
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Cassandra J
authors: CJ
authors: Vandenberg
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Suzanne
authors: S
authors: Cory
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D003630:Daunorubicin / Q000494:pharmacology / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055786:Gene Knockout Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051788:Myeloid-Lymphoid Leukemia Protein; D003630:Daunorubicin