Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.
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We thank Ying Zou, MD, PhD, Nicholas Ambulos, PhD and Danielle Sewell, MSRS of the Genomics Shared Service of University of Maryland School of Medicine for validating the cell lines by short tandem repeat analysis and karyotyping them. We thank Xiaoxuan Fan, PhD and Bryan Hahn, BS of the Flow Cytometry Shared Service at UMGCCC for helping to sort the YFP-positive cells after transduction and the Center for Translational Research in Imaging for access to Xenogen. The CRISPR Core at UMGCCC packaged the plasmid into lentiviruses.
This study was supported by a research grant provided by Jazz Pharmaceuticals to AE. This work was partially supported by the University of Maryland Greenebaum Comprehensive Cancer Center Support grant (P30CA134274) and the State of Maryland’s Cigarette Restitution Funds.
Conflict of interest
AE has received research grants from Jazz Pharmaceuticals and NewLink Genetics. AE is a global oncology advisory board member for Amgen and has served as an advisory board member for Genentech and Servier. AE and RGL are Co-Founders and Scientific Advisors for KinaRx, LLC. All other authors declare that they have no relevant competing interests.
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Emadi, A., Kapadia, B., Bollino, D. et al. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01080-6