Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.

Leukemia
Ashkan EmadiRena G Lapidus

Abstract

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 t...Continue Reading

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Citations

Mar 4, 2021·Pharmaceuticals·Kanwal Mahmood, Ashkan Emadi
Jun 29, 2021·Frontiers in Oncology·Bradley StockardJatinder K Lamba
Jul 20, 2021·Frontiers in Cell and Developmental Biology·Martina ChiuOvidio Bussolati

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Software Mentioned

GraphPad Prism
FCS Express
Excel
HTSeq count
QuantStudio
Compusyn
Ion Reporter
FastQC
R package “ DESeq ”
DESeq

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