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

Abstract 1567

Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they are believed to promote JAK2-oligomerization and autonomous signalling although the underlying mechanisms remain unclear. Affected entities are candidates for therapy with JAK2 signalling inhibitors. Among 200 peripheral T-cell lymphomas surveyed, we identified only two with JAK2 amplification and none with JAK2 translocations, confirming their rarity in T-cell neoplasias. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in cell lines established at indolent and aggressive phases of a cutaneous T-cell lymphoma. To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 genes most upregulated in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive phase cells, was partially restored by PCM1-JAK2 knockdown. Activation of the tumor suppressor SOCS3 by PCM1-JAK2 may follow structural alteration of JAK2 affecting the ternary complex it forms with SOCS3 and receptor proteins. Treatment with JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive mimicked knockdown results, highlighting JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5 as reported for JAK2V617F or ETV6/TEL-JAK2, thus extending the paradigm of STAT5 activation by JAK2 alterations in hematopoietic malignancies. MAC-1/2A/2B are the first JAK2– translocation cell line models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.