The PTP1B mutant PTP1B∆2-4 is a positive regulator of the JAK/STAT signalling pathway in Hodgkin lymphoma.

The neoplastic Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) depend on chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways to maintain survival and proliferation. Accumulating reports highlight the importance of the inactivation or reduced expression of negative JAK/STAT regulators such as the protein-tyrosine phosphatase 1B (PTP1B/PTPN1) in this process. Various PTPN1 mRNA variants as well as truncated PTP1B proteins were identified in cHL cell lines and primary cHL tumour samples. These PTPN1 mRNA variants lack either one or several exon sequences and therefore render these PTP1B variants catalytically inactive. Here, we show that one of these mutants, PTP1B∆2-4, is not only a catalytically inactive variant, but also augmented the IL-4-induced JAK/STAT activity similar to the recently reported PTP1B∆6 splice variant. Moreover, while PTP1B∆6 diminished the activity and protein levels of PTP1BWT, PTP1BWT remained unaffected by PTP1B∆2-4, arguing for different molecular mechanisms of JAK/STAT modulation by PTP1B∆6 and PTP1B∆2-4. Collectively, these data indicate that PTPN1 variants missing one or more exon sequences originated either from alternative splicing or from gene mutation, create PTP1B gain-of-function variants with oncogenic potential by augmenting JAK/STAT signalling in cHL.