title: Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis.
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.
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY;
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain;
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY;
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Human Oncology and Pathogenesis Program, and.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Patel
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brunel
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Massachusetts General Hospital, Cancer Center and Department of Pathology, Boston, MA;
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pretz
authors.affiliation: Human Oncology and Pathogenesis Program, and.
authors.forename: Jihae
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Human Oncology and Pathogenesis Program, and.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland;
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.affiliation: Research Centre, Maisonneuve-Rosemont Hospital, Department of Hematology, Maisonneuve-Rosemont Hospital, and University of Montreal, Montreal, QC, Canada;
authors.forename: Lambert
authors.initials: L
authors.lastname: Busque
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.affiliation: 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.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: 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.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY;
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D037282:Calreticulin; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D037282:Calreticulin; D050791:STAT Transcription Factors; D053614:Janus Kinase 2; D053612:Janus Kinases
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