: FTY720 (Fingolimod) is an immunosuppressive drug approved by FDA for Multiple Sclerosis (MS), that has gained attention as anti-cancer drug, thanks to its ability to disrupt the binding between the onco-protein SET and the tumor- suppressor phosphatase PP2A. We investigated FTY720 induced phospho-proteomic changes on acute myeloid leukemia cell lines carrying KMT2A-transocations. The phospho-proteomic data indicated that FTY720 treatment resulted in the down-regulation of phospho-sites associated to protein serine/threonine kinase activity, chromatin organisation and transcription. The findings support the hypothesis of a feedback loop between SET, PP2A and MYC, whereby FTY720 re-activates PP2A with an overall inhibitory effect on MYC, resulting in cell cycle arrest and apoptosis.