Targeting PTPN2-mediated dephosphorylation destabilizes c-MYC and suppresses acute myeloid leukemia survival

Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knockdown of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and c-MYC, establishing c-MYC as a direct acting substrate of PTPN2. Then, we obtained a small-molecule inhibitor, WS35, which has good inhibitory activity against PTPN2. Moreover, WS35 shows a strong therapeutic effect in vivo for AML. In conclusion, these results indicate the carcinogenic mechanism of PTPN2, and the therapeutic strategies targeting PTPN2 have significant potential for treating AML.