2.50
Hdl Handle:
http://hdl.handle.net/10033/271304
Title:
t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5.
Authors:
Ehrentraut, Stefan; Nagel, Stefan; Scherr, Michaela E; Schneider, Björn; Quentmeier, Hilmar; Geffers, Robert; Kaufmann, Maren; Meyer, Corinna; Prochorec-Sobieszek, Monika; Ketterling, Rhett P; Knudson, Ryan A; Feldman, Andrew L; Kadin, Marshall E; Drexler, Hans G; Macleod, Roderick A F
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.
Affiliation:
Leibniz Institute, DSMZ - German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
Citation:
t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. 2013, 8 (1):e53767 PLoS ONE
Journal:
PloS one
Issue Date:
2013
URI:
http://hdl.handle.net/10033/271304
DOI:
10.1371/journal.pone.0053767
PubMed ID:
23372669
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorEhrentraut, Stefanen_GB
dc.contributor.authorNagel, Stefanen_GB
dc.contributor.authorScherr, Michaela Een_GB
dc.contributor.authorSchneider, Björnen_GB
dc.contributor.authorQuentmeier, Hilmaren_GB
dc.contributor.authorGeffers, Roberten_GB
dc.contributor.authorKaufmann, Marenen_GB
dc.contributor.authorMeyer, Corinnaen_GB
dc.contributor.authorProchorec-Sobieszek, Monikaen_GB
dc.contributor.authorKetterling, Rhett Pen_GB
dc.contributor.authorKnudson, Ryan Aen_GB
dc.contributor.authorFeldman, Andrew Len_GB
dc.contributor.authorKadin, Marshall Een_GB
dc.contributor.authorDrexler, Hans Gen_GB
dc.contributor.authorMacleod, Roderick A Fen_GB
dc.date.accessioned2013-03-06T13:57:14Z-
dc.date.available2013-03-06T13:57:14Z-
dc.date.issued2013-
dc.identifier.citationt(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. 2013, 8 (1):e53767 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid23372669-
dc.identifier.doi10.1371/journal.pone.0053767-
dc.identifier.urihttp://hdl.handle.net/10033/271304-
dc.description.abstractFusions 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.titlet(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5.en
dc.typeArticleen
dc.contributor.departmentLeibniz Institute, DSMZ - German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.en_GB
dc.identifier.journalPloS oneen_GB

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