t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5
- PMID: 23372669
- PMCID: PMC3553112
- DOI: 10.1371/journal.pone.0053767
t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5
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.
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References
-
- Hoeller S, Walz C, Reiter A, Dirnhofer S, Tzankov A (2011) PCM1-JAK2-fusion: a potential treatment target in myelodysplastic-myeloproliferative and other hemato-lymphoid neoplasms. Expert Opin Ther Targets 15: 53–62. - PubMed
-
- Radtke S, Haan S, Jorissen A, Hermanns HM, Diefenbach S, et al. (2005) The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression. J Biol Chem 280: 25760–25768. - PubMed
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