KMT2A degradation is observed in decitabine-responsive acute lymphoblastic leukemia cells.

Hypermethylation of tumor suppressor genes is a hallmark of leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine-5)-methyltransferase 1 (DNMT1). Structural similarities within DNA-binding domains of DNMT1, and the leukemic driver histone-lysine N-methyltransferase 2A (KMT2A) suggest that decitabine might also affect the latter. In acute lymphoblastic leukemia (ALL) cell lines, and xenograft models, we observed increased DNMT1, and KMT2A expression in response to decitabine-induced demethylation. Strikingly, KMT2A protein expression was diminished in all cell lines that experienced DNMT1 degradation. Moreover, only cells with reduced KMT2A protein levels showed biological effects following decitabine treatment. KMT2A wild-type, and rearranged cells were locked in G2 and G1 cell cycle phases, respectively, likely due to p27/p16 activation. Primary sample gene expression profiling confirmed different patterns between KMT2A wild-type, and translocated cells. This newly discovered decitabine mode of action via KMT2A degradation evokes anti-leukemic activity in adult ALL cells, and can act synergistically with menin inhibition. Following the successful clinical implementation of decitabine for acute myeloid leukemia, the drug should be considered a potential promising addition to the therapeutic portfolio for ALL as well.