t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.
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.
Leibniz Institute, DSMZ-German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
Stefan
S
Ehrentraut
Stefan
S
Nagel
Michaela E
ME
Scherr
Björn
B
Schneider
Hilmar
H
Quentmeier
Robert
R
Geffers
Maren
M
Kaufmann
Corinna
C
Meyer
Monika
M
Prochorec-Sobieszek
Rhett P
RP
Ketterling
Ryan A
RA
Knudson
Andrew L
AL
Feldman
Marshall E
ME
Kadin
Hans G
HG
Drexler
Roderick A F
RA
MacLeod
D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8; D002899:Chromosomes, Human, Pair 9; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D000096926:Benzenesulfonamides
D050990:GATA3 Transcription Factor; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C494749:GATA3 protein, human; C575876:PCM1-JAK2 fusion protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; C528327:fedratinib; D000096926:Benzenesulfonamides