Receptor-type tyrosine-protein phosphatase kappa promoter hypermethylation correlates with unfavorable prognosis in nasal NK/T-cell lymphoma patients treated with SMILE regimen

Abstract

One of the main characteristics of nasal NK/T-cell lymphoma (NKTCL) is the constitutive activation of signal transducer and activator of transcription 3 (STAT3) and frequent deletions on chromosome 6q. Tyrosine phosphorylation at Tyr705 is required for STAT3 to bind to specific DNA target sites. Here we first investigated whether receptor-type tyrosine-protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. We found a strong in vivo correlation between low PTPRK expression and high nuclear phospho-STAT3Tyr705 levels in NKTCL primary tumors and showed that PTPRK binds to STAT3 and directly dephosphorylates phospho-STAT3 at Tyr705 and regulates the levels of phospho-STAT3Tyr705 in NKTCL. Further studies showed that monoallelic deletion and promoter hypermethylation causes underexpression of PTPRK mRNA in NKTCL, and methylation of PTPRK promoter significantly correlates with higher IPI (p<0.001) and with inferior overall survival (p=0.049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis and that methylation of the PTPRK promoter correlates with a severe clinical course and worse prognosis in NKTCL patients treated with the SMILE protocol.