Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is sustained by leukemia-initiating cells (LICs). While PTP4A2 phosphatase, as known as PRL2, is highly expressed in AML, the mechanisms by which PTP4A2 promotes leukemogenesis are largely unexplored. In this study, we demonstrate that PTP4A2 promotes AML by inhibiting the p53 tumor suppressor pathway in LICs. Using KMT2A-MLLT3-driven AML as a model, we found that PTP4A2 deficiency activates p53 and induces LIC apoptosis and senescence, thereby extending the survival of recipient mice repopulated with Ptp4a2-/- LICs. Mechanistically, PTP4A2 directly interacts with p53 and dephosphorylates it at serine 392, decreasing p53 stability and activity to enhance LIC proliferation and survival. Collectively, our findings identify p53 as a potential PTP4A2 substrate in leukemia cells and uncover a novel mechanism by which PTP4A2 enhances LIC maintenance.
Xiao et al. (Wed,) studied this question.