Abstract
Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3–23.3 (n=1), 9q33.1–34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31–36.33 (n=6), 17q21.2–q21.31 (n=5) and 17q25.1–25.3 (n=5) and deletions affecting 18p11.31–11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non-canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a ‘HSC signature' (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal.
Highlights
The Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic disorders characterized by the overproduction of blood cells belonging to the myeloid, megakaryocytic and/or erythroid lineages.[1]
To identify genes recurrently affected by genomic aberrations in MPN, we hybridized DNA from peripheral blood granulocytes of 87 MPN patients (32 PV, 24 PMF and 31 ET) to Affymetrix 250K single-nucleotide polymorphism (SNP) arrays
We found that several genes mutated in MPN were affected by genomic aberrations in our cohort
Summary
The Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic disorders characterized by the overproduction of blood cells belonging to the myeloid, megakaryocytic and/or erythroid lineages.[1]. The log[2] ratio of the intensity patients, genomic copy number changes could be correlated for each SNP for each sample relative to data from 60 with gene expression in granulocytes, leading to the identifica- unrelated CEU subjects of HapMap project JAK2 against the dCT (Ct-JAK2V617F-CtJAK2WT) was generated clustering of genome-wide copy number change profiles was using DNA from a healthy control and a PV erythroid colony performed in PV, ET and PMF patients using the distance of homozygous for the JAK2V617F mutation. For JAK2 inhibition studies, HEL and UKE-1 cells were treated with either JAK inhibitor I (Calbiochem, Gibbstown, NJ, USA) or NVP-BSK805 Inhibitor (1–2 mM) (Novartis, Schaumberg, IL, USA), respectively, for 16 h, using dimethylsulphoxide as a control
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