Mastl Is a New Therapeutic Target for Acute Myeloid Leukemia

Recently, the approval of several new generation of targeted therapeutic agents greatly improved the prognosis of Acute myeloid leukemia (AML). Despite of these undeniable progresses, many patients still lack effective therapies. Moreover, resistance to the targeted agents represent major clinical challenges. Therefore, there is an unmet need to discover new therapeutic targets and overcome the resistance. In this study, our strategy is to discover a specific kinase, which can be served as monotherapy and also overcoming resistance to current venetoclax-based therapies. Through high-throughput screening of a custom kinase inhibitor library of 500 compounds and re-analyzing genome-wide CRISPR/Cas9 screen data sets, we identified Microtubule Associated Serine/Threonine Kinase Like (MASTL) as a potential novel target for AML treatment. Public data and our in house data showed MASTL expression was significantly higher in AML patients than healthy subjects. RNAi and pharmacologic inhibition of MASTL reduced cell viability and colony formation in THP-1 and OCI-AML3 cells. MASTL knock down and MASTL inhibitor significantly reduced tumor growth in THP-1 derived subcutaneous tumor model and prolonged survival in xenograft NCG mouse model. Mechanistically, MASTL knock down induced downregulation of Survivin and upregulation of Puma in THP-1 cells. Transcriptome analysis showed MASTL suppression was associated with several signaling pathways including Rap1, Toll-like receptor, MAPK, TNF signaling pathway. Importantly, MASTL knock down dramatically suppressed the expression of S100A8 and S100A9, which is known to be involved in venetoclax resistance in AML. Both genetic and pharmacologic inhibition of MASTL reversed venetoclax resistance in venetoclax resistant cell lines. The combination of venetoclax and MASTL inhibitor significantly reduced tumor growth than each monotherapy in vivo. In conclusion, our data suggest that MASTL inhibition is a promising strategy for AML treatment. Moreover, MASTL inhibition potentiates venetoclax response and overcome venetoclax resistance in AML.