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Blood DOI:10.1182/blood-2014-02-554634

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

Publication TypeJournal Article
Year of Publication2014
AuthorsRampal, R, Al-Shahrour, F, Abdel-Wahab, O, Patel, JP, Brunel, J-P, Mermel, CH, Bass, AJ, Pretz, J, Ahn, J, Hricik, T, Kilpivaara, O, Wadleigh, M, Busque, L, D Gilliland, G, Golub, TR, Ebert, BL, Levine, RL
Date Published2014 May 29
KeywordsCalreticulin, Case-Control Studies, Cell Transformation, Neoplastic, Cluster Analysis, Female, Gene Expression Profiling, Genomics, Homozygote, Humans, Janus Kinase 2, Janus Kinases, Male, Mutation, Myeloproliferative Disorders, Signal Transduction, STAT Transcription Factors, Transcriptome

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.


Alternate JournalBlood
PubMed ID24740812
PubMed Central IDPMC4041169
Grant ListR01 CA151949 / CA / NCI NIH HHS / United States
1R01CA151949-01 / CA / NCI NIH HHS / United States