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

Stefan Ehrentraut, Stefan Nagel, Michaela E. Scherr, Björn Schneider, Hilmar Quentmeier, Robert Geffers, Maren Kaufmann, Corinna Meyer, Monika Prochorec-Sobieszek, Rhett P. Ketterling, Ryan A. Knudson, Andrew L Feldman, Marshall E. Kadin, Hans G. Drexler, Roderick A F MacLeod

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere53767
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 29 2013

Fingerprint

lymphoma
T-lymphocytes
T-cells
Cutaneous T-Cell Lymphoma
Lymphoma
leukemia
T-Lymphocytes
Neoplasms
Leukemia
neoplasms
Developmental Genes
Cell Line
cell lines
Sexual Partners
Cells
Myeloid Cells
therapeutics
Transcriptome
Protein-Tyrosine Kinases
disease models

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ehrentraut, S., Nagel, S., Scherr, M. E., Schneider, B., Quentmeier, H., Geffers, R., ... MacLeod, R. A. F. (2013). t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. PLoS One, 8(1), [e53767]. https://doi.org/10.1371/journal.pone.0053767

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

In: PLoS One, Vol. 8, No. 1, e53767, 29.01.2013.

Research output: Contribution to journalArticle

Ehrentraut, S, Nagel, S, Scherr, ME, Schneider, B, Quentmeier, H, Geffers, R, Kaufmann, M, Meyer, C, Prochorec-Sobieszek, M, Ketterling, RP, Knudson, RA, Feldman, AL, Kadin, ME, Drexler, HG & MacLeod, RAF 2013, 't(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5', PLoS One, vol. 8, no. 1, e53767. https://doi.org/10.1371/journal.pone.0053767
Ehrentraut S, Nagel S, Scherr ME, Schneider B, Quentmeier H, Geffers R et al. t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. PLoS One. 2013 Jan 29;8(1). e53767. https://doi.org/10.1371/journal.pone.0053767
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. / t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5. In: PLoS One. 2013 ; Vol. 8, No. 1.
@article{9a4913736fa04de1b0d9ebbed08a2efc,
title = "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.",
author = "Stefan Ehrentraut and Stefan Nagel and Scherr, {Michaela E.} and Bj{\"o}rn Schneider and Hilmar Quentmeier and Robert Geffers and Maren Kaufmann and Corinna Meyer and Monika Prochorec-Sobieszek and Ketterling, {Rhett P.} and Knudson, {Ryan A.} and Feldman, {Andrew L} and Kadin, {Marshall E.} and Drexler, {Hans G.} and MacLeod, {Roderick A F}",
year = "2013",
month = "1",
day = "29",
doi = "10.1371/journal.pone.0053767",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

TY - JOUR

T1 - t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

AU - Ehrentraut, Stefan

AU - Nagel, Stefan

AU - Scherr, Michaela E.

AU - Schneider, Björn

AU - Quentmeier, Hilmar

AU - Geffers, Robert

AU - Kaufmann, Maren

AU - Meyer, Corinna

AU - Prochorec-Sobieszek, Monika

AU - Ketterling, Rhett P.

AU - Knudson, Ryan A.

AU - Feldman, Andrew L

AU - Kadin, Marshall E.

AU - Drexler, Hans G.

AU - MacLeod, Roderick A F

PY - 2013/1/29

Y1 - 2013/1/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84872776180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872776180&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0053767

DO - 10.1371/journal.pone.0053767

M3 - Article

C2 - 23372669

AN - SCOPUS:84872776180

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 1

M1 - e53767

ER -