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MAT2A as key regulator and therapeutic target in MLL leukemogenesis

ABSTRACT: Epigenetic dysregulation plays a pivotal role in MLL pathogenesis, therefore serving as suitable therapeutic point of attack. SAM is the universal methyl donor in human cells and is synthesized by MAT2A. MAT2A is already known to be deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLLr leukemia model, faithfully mimicking MLL patients’ pathology with indefinite growth potential in in vitro culture, to evaluate the unknown role of MAT2A as therapeutic target. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr specific enhanced response to PF-9366, a new MAT2A inhibitor, by alteration of proliferation, viability, differentiation, apoptosis and cell cycling. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases DOT1L and PRMT5, revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141839 | GEO | 2020/06/22

REPOSITORIES: GEO

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