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

PLoS One. 2013;8(1):e53767. doi: 10.1371/journal.pone.0053767. Epub 2013 Jan 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Chromosomes, Human, Pair 8
  • Chromosomes, Human, Pair 9
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Silencing
  • Genetic Vectors
  • Humans
  • Lentivirus / genetics
  • Lymphoma, T-Cell, Cutaneous / genetics*
  • Lymphoma, T-Cell, Cutaneous / metabolism
  • Lymphoma, T-Cell, Cutaneous / pathology
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrrolidines / pharmacology
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / agonists
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Translocation, Genetic

Substances

  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Oncogene Proteins, Fusion
  • PCM1-JAK2 fusion protein, human
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • SOCS2 protein, human
  • SOCS3 protein, human
  • STAT5 Transcription Factor
  • Sulfonamides
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • fedratinib