Mechanisms of Notch signaling silencing in AML. So far, 4 potential levels of silencing of Notch signaling have been identified: (1) AML-initiating cells may reside in niches not expressing Notch ligands; (2) Notch pathway genes might be mutated (so far, only MAML1 mutations have been identified); (3) Notch pathway genes might be epigenetically silenced (for example, HES5, LFNG, and MAML1 have been shown to be hypermethylated in IDH mutant patients; and (4) alternative splicing of Notch pathway genes might lead to expression of inactive isoforms (to date, mis- or alternative-splicing of NOTCH2 and RBP-Jκ have been identified in a large fraction of AML patients).