t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

Stefan Ehrentraut, Stefan Nagel, Michaela E. Scherr, Björn Schneider, Hilmar Quentmeier, Robert Geffers, Maren Kaufmann, Corinna Meyer, Monika Prochorec-Sobieszek, Rhett P. Ketterling, Ryan A. Knudson, Andrew L. Feldman, Marshall E. Kadin, Hans G. Drexler, Roderick A.F. MacLeod

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2-translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.

Original languageEnglish (US)
Article numbere53767
JournalPloS one
Volume8
Issue number1
DOIs
StatePublished - Jan 29 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Ehrentraut, S., Nagel, S., Scherr, M. E., Schneider, B., Quentmeier, H., Geffers, R., Kaufmann, M., Meyer, C., Prochorec-Sobieszek, M., Ketterling, R. P., Knudson, R. A., Feldman, A. L., Kadin, M. E., Drexler, H. G., & MacLeod, R. A. F. (2013). t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. PloS one, 8(1), [e53767]. https://doi.org/10.1371/journal.pone.0053767