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.

SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21

“…Cell cycle checkpoints, which can be activated as a result of DNA damage or exogenous stress signals are cell-intrinsic mechanisms that prevent cells from developing a malignant phenotype. 37 Previous cytogenetic studies revealed an accumulation of chromosome aberrations during the progression from LyP to PCALCL and MF, 25,38,39 indicating an impaired cell-cycle checkpoint during the malignant progression. Our study suggests that the cytogenetic abnormalities during disease progression may be attributed to SATB1 aberrancy-induced G1/S checkpoint disruption in CD30 1 lymphoma cells.…”

“…2 To further quantify SATB1 expression during disease progression, we first studied cells established from a patient who progressed from LyP to PCALCL. 5,25 In this case, the Mac-1 cell line was derived during an indolent course of disease, whereas the Mac-2A and Mac-2B cells were derived from separate rapidly growing skin tumors 3 years later in disease progression. These cells are representative of the primary tumors and retain the features of the original lymphoma.…”

2.4 Cell Line Monitoring: Molecular Cytogenetic Characterization

“…This is where cytogenetics can come to the rescue, at least where karyotypic data have been published, since most cell line karyotypes are effectively unique. That of the anaplastic large cell lymphoma cell line MAC-2A (Figure 2.4.1a, lower panel), although closely related to those of its sister cell lines MAC-1 and MAC-2B, is still readily distinguishable from its siblings [24].…”

Adult systemic anaplastic large-cell lymphoma: recommendations for diagnosis and management

“…Moreover, GEP data may provide further prognostic stratification of PTCLs [45,47]. Finally, although comprehensive profiling of recurrent somatic mutations in ALCL requires further effort, recent data indicate recurrent abnormalities targeting the JAK-STAT pathway, particularly point mutations of JAK1 and STAT3 but also including novel fusion genes [48–50]. These findings suggest a potential target for novel therapeutic approaches in at least some ALCLs.…”