Publication Date:
2018-11-29
Description:
Epigenetic dysregulation is at the heart of Acute Myeloid Leukemia (AML), and its mechanistic understanding holds promise in improving AML dismal prognosis. Modification of chromatin accessibility through post-translational modification of histones alters gene expression activity and is directly dependent on cell metabolism for generation of the modifying groups. Methionine metabolism generates S-adenosyl methionine (SAM), the universal methyl donor in the cell, through the activity of multimeric methionine adenosyl transferase (MAT) enzymes. MAT2A is an obligatory subunit in hematopoietic cells, and we have recently tabled it in a CRISPR drop-out screen [1] as a candidate vulnerability in AML. We have validated the anti-AML effects of MAT2A ablation using shRNA-mediated gene expression knockdown, and could further phenocopy cell line selectivity observed in our CRISPR screen through the use of the MAT2A selective inhibitor FIDAS-5 [2] (IC50 MOLM-13 1.0μM, OCI-AML3 0.7μM, MV4.11 11μM). MAT2A inhibition significantly depleted SAM levels (fold change to DMSO, FC=0.20±0.07; p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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