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

Abstract

Key Points • A gene expression profile consistent with activated JAK2 signaling is seen in all MPN patients, including in patients with CALR mutations. • Transcriptional profiling discriminates subsets of MPNs based on JAK2V617F allele burden and on the presence of CALR and TET2 mutations. 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. (Blood. 2014;123(22):e123-e133) Introduction The Philadelphia-negative myeloproliferative neoplasms (MPN) are hematopoietic disorders characterized by clonal expansion of mature myeloid elements. These include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Genomic analysis of the MPNs has shown frequent mutational events in the JAK-STAT signaling pathway including JAK2V617F mutations in 90% to 95% of patients with PV, and in 50% to 60% of patients with ET and PMF. 1-5 In addition, somatic mutations in the thrombopoietin receptor MPL in a subset of patients with JAK2V617F-negative ET and PMF, JAK2 exon 12 mutations 6,7 in JAK2V617F-negative PV, 8,9 and LNK mutations in JAK2V617F-negative MPN 10-12 have been identified. These genetic data indicate that mutations that lead to constitutive JAK-STAT signaling are a common genetic event in the different MPNs. The identification of mutations in the JAK-STAT pathway in the majority of MPN patients led to the development of JAK inhibitors, and approval by the US Food and Drug Administration of the JAK1/2 inhibitor ruxolitinib for the treatment of myelofibrosis (MF). 13,14 Treatment with ruxolitinib and other JAK kinase inhibitors leads to substantive clinical benefit including marked reduction in spl...

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

“…Intriguingly, GATA1 mRNA expression in megakaryocytes [28], blood CD341 progenitors [29], and mononuclear BM cells [30] were found to be similar in PMF compared with control subjects. Novel information from the NCBI/GEO database has even shown higher GATA1 mRNA expression in whole blood and granulocytes from PMF patients compared with controls (GEO Accession: GSE26049 and GSE54646, unpublished results) [31,32]. GATA1 may also be present in endothelial cells [14], but we could not verify expression in our BM biopsy vessels.…”

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

“…The seminal discovery of activating mutations in CSF3R in CNL, most frequently CSF3RT618I, was rapidly confirmed [2,3]. Similar to the mutually exclusive somatic driver mutations implicated in the classic Philadelphia chromosome negative MPNs (polycythemia vera, essential thrombocythemia and primary myelofibrosis) involving JAK2, MPL, and CALR, the majority of the CSF3R mutations identified also signal through the JAK-STAT pathway [2,4,5]. Cooperative subclonal gene mutations of potential prognostic significance have been identified in the classic MPNs such as SETBP1 and ASXL1, but their role in CNL remains to be defined [3,6,7].…”

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…JAK-STAT activation might be the central theme in MPN pathogenesis [46]. JAK2 and MPL mutations are believed to directly activate JAK-STAT whereas CALR mutations might do the same indirectly, although mouse models suggest a primary effect on platelet production [47].…”