Journal article
Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice
NS Anstee, RA Bilardi, AP Ng, Z Xu, M Robati, CJ Vandenberg, S Cory
Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2019
Abstract
Many acute myeloid leukaemias (AMLs) express high levels of BCL-2 and MCL-1, especially after therapy. To test the impact of these anti-apoptotic proteins on AML development and treatment, we used haemopoietic reconstitution to generate MLL-AF9 AMLs expressing BCL-2 or Mcl-1 transgenes. AMLs with elevated BCL-2 or MCL-1 had a higher proportion of mature myeloid cells but, like conventional MLL-AF9 AMLs, were readily transplantable. Short-term cell lines established from multiple primary AMLs of each genotype were tested in vitro for susceptibility to chemotherapeutics currently used for treating AML (daunorubicin, etoposide, cytarabine); the proteasome inhibitor bortezomib; CDK7/9 inhibitors..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank our colleagues JM Adams, A Wei and A Strasser for review of the manuscript; S Glaser, H Jousset, David Huang, K Lowes, D Segal and C Burns for advice and reagents; M Robati, P Novello, G Siciliano, K Hughes, J Corbin and J McManus for technical assistance and mouse husbandry; and the institute's flow cytometry and histology facilities for skilled support. This work was supported by funding from the NHMRC (Australia) (program grants 1016701, 113577 and project grants 1058746, 1122783); US Leukaemia and Lymphoma Society Specialized Center for Research Grant 7001-13; Leukaemia Foundation of Australia; and infrastructure support to the institute from the NHMRC Independent Research Institute Infrastructure Support Scheme (IRISS 9000220) and the Victorian State Government Operational Infrastructure Support (OIS).