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Blood. 2014 May 29;123(22):e123-33. doi: 10.1182/blood-2014-02-554634. Epub 2014 Apr 16.

Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis.

Author information

1
Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY;
2
Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain;
3
Human Oncology and Pathogenesis Program, and.
4
Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA;
5
Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Massachusetts General Hospital, Cancer Center and Department of Pathology, Boston, MA;
6
Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA;
7
Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland;
8
Dana-Farber Cancer Institute, Boston, MA;
9
Research Centre, Maisonneuve-Rosemont Hospital, Department of Hematology, Maisonneuve-Rosemont Hospital, and University of Montreal, Montreal, QC, Canada;
10
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
11
Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Children's Hospital, Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MD; and.
12
Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Abstract

Genomic studies have identified somatic alterations in the majority of myeloproliferative neoplasms (MPN) patients, including JAK2 mutations in the majority of MPN patients and CALR mutations in JAK2-negative MPN patients. However, the role of JAK-STAT pathway activation in different MPNs, and in patients without JAK2 mutations, has not been definitively delineated. We used expression profiling, single nucleotide polymorphism arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in all MPN patients regardless of clinical phenotype or mutational status. In addition, the activated JAK2 signature was present in patients with somatic CALR mutations. Conversely, we identified a gene expression signature of CALR mutations; this signature was significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK2 mutational status, are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis.

PMID:
24740812
PMCID:
PMC4041169
DOI:
10.1182/blood-2014-02-554634
[Indexed for MEDLINE]
Free PMC Article

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