JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling

Sven Schwemmers, Britta Will, Cornelius F. Waller, Khadija Abdulkarim, Peter Johansson, Björn Andreasson, Heike L. Pahl

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objective: Presence of the JAK2V617F mutation in only 40% to 60% of patients with essential thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, polycythemia vera, and idiopathic myelofibrosis. Analogous to JAK2,V617F these mutations cause constitutive JAK2 and signal transducer and activation of transcription (STAT) activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/STAT signal transduction pathway, underlie a subset of JAK2V617F-negative ET. Methods: cDNA microarrays and quantitative reverse transcriptase polymerase chain reactions were used to compare gene expression in 40 ET patients with and without the JAK2V617F mutation. Results: Unsupervised clustering of gene-expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2V617F mutation. Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation. Conclusions: These data demonstrate that a large proportion of JAK2V617F-negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ET-inducing changes will facilitate both a molecular classification of ET and development of rationally designed therapies.

Original languageEnglish (US)
Pages (from-to)1695-1703
Number of pages9
JournalExperimental Hematology
Volume35
Issue number11
DOIs
StatePublished - Nov 2007
Externally publishedYes

Fingerprint

Essential Thrombocythemia
Transducers
Transcriptional Activation
Mutation
Signal Transduction
Gene Expression
Myeloproliferative Disorders
Polycythemia Vera
Primary Myelofibrosis
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Cluster Analysis
Exons
Phosphorylation
Cytokines
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Schwemmers, S., Will, B., Waller, C. F., Abdulkarim, K., Johansson, P., Andreasson, B., & Pahl, H. L. (2007). JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling. Experimental Hematology, 35(11), 1695-1703. https://doi.org/10.1016/j.exphem.2007.07.004

JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling. / Schwemmers, Sven; Will, Britta; Waller, Cornelius F.; Abdulkarim, Khadija; Johansson, Peter; Andreasson, Björn; Pahl, Heike L.

In: Experimental Hematology, Vol. 35, No. 11, 11.2007, p. 1695-1703.

Research output: Contribution to journalArticle

Schwemmers, S, Will, B, Waller, CF, Abdulkarim, K, Johansson, P, Andreasson, B & Pahl, HL 2007, 'JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling', Experimental Hematology, vol. 35, no. 11, pp. 1695-1703. https://doi.org/10.1016/j.exphem.2007.07.004
Schwemmers, Sven ; Will, Britta ; Waller, Cornelius F. ; Abdulkarim, Khadija ; Johansson, Peter ; Andreasson, Björn ; Pahl, Heike L. / JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling. In: Experimental Hematology. 2007 ; Vol. 35, No. 11. pp. 1695-1703.
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abstract = "Objective: Presence of the JAK2V617F mutation in only 40{\%} to 60{\%} of patients with essential thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, polycythemia vera, and idiopathic myelofibrosis. Analogous to JAK2,V617F these mutations cause constitutive JAK2 and signal transducer and activation of transcription (STAT) activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/STAT signal transduction pathway, underlie a subset of JAK2V617F-negative ET. Methods: cDNA microarrays and quantitative reverse transcriptase polymerase chain reactions were used to compare gene expression in 40 ET patients with and without the JAK2V617F mutation. Results: Unsupervised clustering of gene-expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2V617F mutation. Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation. Conclusions: These data demonstrate that a large proportion of JAK2V617F-negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ET-inducing changes will facilitate both a molecular classification of ET and development of rationally designed therapies.",
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AU - Schwemmers, Sven

AU - Will, Britta

AU - Waller, Cornelius F.

AU - Abdulkarim, Khadija

AU - Johansson, Peter

AU - Andreasson, Björn

AU - Pahl, Heike L.

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N2 - Objective: Presence of the JAK2V617F mutation in only 40% to 60% of patients with essential thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, polycythemia vera, and idiopathic myelofibrosis. Analogous to JAK2,V617F these mutations cause constitutive JAK2 and signal transducer and activation of transcription (STAT) activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/STAT signal transduction pathway, underlie a subset of JAK2V617F-negative ET. Methods: cDNA microarrays and quantitative reverse transcriptase polymerase chain reactions were used to compare gene expression in 40 ET patients with and without the JAK2V617F mutation. Results: Unsupervised clustering of gene-expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2V617F mutation. Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation. Conclusions: These data demonstrate that a large proportion of JAK2V617F-negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ET-inducing changes will facilitate both a molecular classification of ET and development of rationally designed therapies.

AB - Objective: Presence of the JAK2V617F mutation in only 40% to 60% of patients with essential thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, polycythemia vera, and idiopathic myelofibrosis. Analogous to JAK2,V617F these mutations cause constitutive JAK2 and signal transducer and activation of transcription (STAT) activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/STAT signal transduction pathway, underlie a subset of JAK2V617F-negative ET. Methods: cDNA microarrays and quantitative reverse transcriptase polymerase chain reactions were used to compare gene expression in 40 ET patients with and without the JAK2V617F mutation. Results: Unsupervised clustering of gene-expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2V617F mutation. Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation. Conclusions: These data demonstrate that a large proportion of JAK2V617F-negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ET-inducing changes will facilitate both a molecular classification of ET and development of rationally designed therapies.

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