title: A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells.
abstract: Chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways is a hallmark of a variety of B-cell lymphomas, including classical Hodgkin lymphoma (cHL). Constitutive JAK/STAT signaling is crucial for survival and proliferation of Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of cHL. Although the molecular basis of this constitutive JAK/STAT signaling in cHL has not been completely understood, accumulating reports highlight the role of an inactivation or reduced expression of negative JAK/STAT regulators such as silencer of cell signaling 1 (SOCS1) or protein-tyrosine phosphatase 1B (PTP1B) in this process. Here, we report the expression of truncated PTP1B mRNA variants identified in cHL cell lines and primary cHL tumor samples lacking either 1 or several exon sequences. One of these novel PTP1B variants, a splice variant lacking exon 6 (PTP1BΔ6), was found expressed at low levels in cHL cell lines. However, serum stimulation of cHL augmented the expression of PTP1BΔ6 significantly. Functional characterization of PTP1BΔ6 revealed a positive effect on interferon-γ- and interleukin-4-induced JAK/STAT activity in HEK293 or HEK293-STAT6 cells, and on the basal STAT activity in stably transfected L-428 and U-HO1 cHL cell lines. Furthermore, PTP1BΔ6 expression increased the proliferation of L-428 and U-HO1 cells and reduced cytotoxic effects of the chemotherapeutical agents gemcitabine and etoposide distinctively. Collectively, these data indicate that PTP1BΔ6 is a positive regulator of JAK/STAT signaling in cHL.
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Malena
authors.initials: M
authors.lastname: Zahn
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Marienfeld
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Melzner
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Renner
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Wegener
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Mießner
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Karola
authors.initials: K
authors.lastname: Dorsch
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.affiliation: Institute of Pathology, Ulm University, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D049109:Cell Proliferation; D057809:HEK293 Cells; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D053612:Janus Kinases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1