The relationship of JAK2(V617F) and acquired UPD at chromosome 9p in polycythemia vera.

摘要: Letter to the Editor JAK2V617F mutation is most common somatic event observed in patients with myeloproliferative neoplasms (MPN)1-4. JAK2V617F found over 95% of polycythemia vera (PV), 55% essential thrombocytosis and 65% primary myelofibrosis. Homozygous present about half PV whereas it rarely seen other MPNs3, 5, 6. Patients bearing homozygous tend have a longer duration disease2, higher hemoglobin levels, increased incidence pruritis7 are more likely progress post-PV myelofibrosis8. shown result from mitotic recombination, leading acquired uniparental disomy (aUPD) on chromosome 9p9. It was reported that JAK2 46/1 (GGCC) haplotype may predispose carriers mutation10-12, facilitates acquisition JAK29, 13. Challenging this view single study reporting 9p aUPD two subjects wild-type JAK214, suggesting these individuals, might preceded JAK2V617F. However, relationship between aUPD, frequency stability existing genotypes has yet be systematically defined larger cohort. To address this, we performed whole-exome sequencing SNP array 31 patients, further validated our findings additional cohorts totaling 59 (Supplementary Methods). In addition, investigated using 36 longitudinal samples. The allelic fraction granulocytes (GNC), measured by sequencing, varied 0.01 1.0 (Figure 1). spanning locus 48% discovery set. The genomes harboring given GNC sample, 0.08 Based quantitative 4 subgroups finding extended Across three cohorts, 42% harbored heterozygous state without detectable (Subgroup I); 45% had an direct proportion level II; JAK2V617F); 10% at approximately twice burden III; JAK2V617F). Although any patient Subgroup III, taken isolation, could explained as mixture cells I II, best explanation for pattern III across reside same cell all such patients. Thus, comprises novel subtype not been previously described. Three (3%) exhibited trisomy 9p, generating 2 copies allele IV). number IV too small thus group evaluated further. Figure 1 The mutational aUPD We then each genotype samples. JAK2V617:9p ratio remained stable in, 11 17 although JAK2V617 itself 2A). contrast, 6 changed their membership. PV1, PV16, PV27 progressed prognostically favorable less clones (Figures 2B-C). For example, Subgroup-I -II first timepoint but four years later only Subgroup-II clone apparent. PV2, PV28 PV31 transformed gained new 2D-E). PV2 eliminated, possibly treatment, Subgroup-III emerged. It interesting myelofibrosis (MF) none 14 or showed phenotype transformation. suggested were develop MF2, propensity also Figure Among those MF, samples collected PV31. We that, both there outgrowth 2D). establish sequential order events. Figure 2 The genotypes We propose pathways 2F) explain results. stem self-renewing progenitors, majority acquire first. Approximately them remain configuration I). Others pathway duplicate one different mechanisms: minor duplicated JAK2V617F-bearing produce Almost via recombination II). progression II factors controlling ascertained analysis. followed mutation, yielding III. case study14, did observe alone unselected 3 asymptomatic until female which included her almost complete low (0.24), indicating composed 2). Further, X-chromosome FHL1 gene clonal transactional clonality assay15. This probably transient Since suggests acquiring would provide proliferative advantage. didn't significant difference 3). The region, patient, includes many genes 4). event(s) generation rare alleles lost. reasoned recurrent loss within regions underwent selection phenotype. Forty-eight lost least 5). them, 9 related division, 7 transcriptional regulation, epigenetic regulation potential tumor suppressors. KDM4C SMARCA2, whichare involved histone modification chromatin remodeling, among them. Moreover, top 10 Table 1) play functional role division. DOCK8, intracellular signaling networks, loss-of-function germline variant. Recent evaluation heterozygosity 3131 tumors absence clear driver mutations led Elledge coworkers hypothesize existence cancer islands16. These multiple act coordinated fashion strong tumorigenic effect. observations suggest region than contribute pathophysiology. Heretofore, zygosity estimated arbitrary threshold >0.5 <0.5 heterozygotes. approach assumed pure population, often case. study, account purity comparing cell, rather absolute burden, accurate determination mutant zygosity. With measure zygosity, can classified 1), setting stage precise analysis prognostic value well improved resolution status patient's tumor. For time, genotypes. Two thirds apparently years. represented One third changes, emergence patterns 2B-E). size investigate treatment regimen clearly important question. Further clinical properties cohort compared required elucidate contribution therein pathogenesis. perspective molecular basis evolution should lead better understanding roles disease.