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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.