The non-receptor protein tyrosine phosphatases gene family (PTPNs) is involved in the tumorigenesis and development of many cancers, but the role of PTPNs in acute myeloid leukemia (AML) remains unclear. After a comprehensive evaluation on the expression patterns and immunological effects of PTPNs using a pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas, the most valuable gene PTPN2 was discovered. Further investigation of the expression patterns of PTPN2 in different tissues and cells showed a robust correlation with AML. PTPN2 was then systematically correlated with immunological signatures in the AML tumor microenvironment and its differential expression was verified using clinical samples. In addition, a prediction model, being validated and compared with other models, was developed in our research. The systematic analysis of PTPN family reveals that the effect of PTPNs on cancer may be correlated to mediating cell cycle-related pathways. It was then found that PTPN2 was highly expressed in hematologic diseases and bone marrow tissues, and its differential expression in AML patients and normal humans was verified by clinical samples. Based on its correlation with immune infiltrates, immunomodulators, and immune checkpoint, PTPN2 was found to be a reliable biomarker in the immunotherapy cohort and a prognostic predictor of AML. And PTPN2'riskscore can accurately predict the prognosis and response of cancer immunotherapy. These findings revealed the correlation between PTPNs and immunophenotype, which may be related to cell cycle. PTPN2 was differentially expressed between clinical AML patients and normal people. It is a diagnostic biomarker and potentially therapeutic target, providing targeted guidance for clinical treatment.