Advertisement

A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells

Malena Zahn, Ralf Marienfeld, Ingo Melzner, Janine Heinrich, Benjamin Renner, Silke Wegener, Anna Mießner, Thomas F. E. Barth, Karola Dorsch, Silke Brüderlein and Peter Möller

Key Points

  • A novel PTP1B variant, PTP1BΔ6, is expressed in cHL cell lines and tumor samples.

  • PTP1BΔ6 augments JAK/STAT activity, cell proliferation, and survival in cHL cell lines.

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.

  • Submitted June 16, 2016.
  • Accepted January 2, 2017.
View Full Text