Journal article

Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice

Natasha S Anstee, Rebecca A Bilardi, Ashley P Ng, Zhen Xu, Mikara Robati, Cassandra J Vandenberg, Suzanne 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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Grants

Awarded by NHMRC (Australia)


Awarded by US Leukaemia and Lymphoma Society Specialized Center for Research Grant


Awarded by NHMRC Independent Research Institute Infrastructure Support Scheme


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).