Cooccurring JAK2 V617F and R1063H mutations increase JAK2 signaling and neutrophilia in myeloproliferative neoplasms

0502682 - ÚMG 2019 RIV US eng J - Journal Article
Mambet, C. - Babošová, Oľga - Defour, J.P. - Leroy, E. - Necula, L. - Stanca, O. - Tatic, A. - Berbec, N. - Coriu, D. - Belickova, M. - Králová, B. - Láníková, Lucie - Veselá, J. - Pecquet, C. - Saussoy, P. - Havelange, V. - Diaconu, C.C. - Divoký, V. - Constantinescu, S.N.
Cooccurring JAK2 V617F and R1063H mutations increase JAK2 signaling and neutrophilia in myeloproliferative neoplasms.
Blood. Roč. 132, č. 25 (2018), s. 2695-2699. ISSN 0006-4971. E-ISSN 1528-0020
R&D Projects: GA ČR GA17-05988S; GA MŠMT LO1220
Institutional support: RVO:68378050
Keywords : essential thrombocythemia * polycythemia-vera
OECD category: Biochemistry and molecular biology
Impact factor: 16.601, year: 2018

Clinical consequences of driver mutations in myeloproliferative neoplasms (MPNs) are well established, yet little is known about the impact of co-occurring JAK2 variants. We tested a cohort of 390 JAK2 V617F-positive MPN patients for JAK2 R1063H, a variant previously described in polycythemia vera (PV) and hereditary erythrocytosis. We identified 14 carriers of both JAK2 V617F and JAK2 R1063H mutations. From the clinical perspective, the double-positive patients exhibited predominantly an essential thrombocythemia (ET) phenotype that was accompanied by significantly higher neutrophil granulocyte counts and hemoglobin values, when compared to those harboring only JAK2 V617F mutation. By employing targeted next generation sequencing for genes known to be involved in myeloid malignancies we found that the mutational profile and the number of additional somatic mutations in double-mutant patients compared to single mutation carriers was comparable. Quantification of R1063H allele in the genomic DNA samples indicated that the variant was inherited in 8 cases, with an allele burden around 50%. In 3 patients with high JAK2 V617F allelic burden, the JAK2 R1063H was nearly homozygous (>80%), suggesting the acquisition of the second allele by uniparental disomy (UPD). In 3 other patients who exhibited trans configuration of JAK2 mutations, low R1063H allele burden was found (allele percentage between 20.7% - 31.5%). Using a combined array-comparative genomic hybridization/single-nucleotide polymorphism assay we detected UPD in 2 out of 3 samples, raising the hypotheses that R1063H was inherited (partially lost due to UPD of the V617F-non-R1063H clone) in 2 patients and acquired in in one patient with low JAK2 R1063H allelic burden. Our functional studies demonstrated that the JAK2 V617F-induced signaling via dimeric myeloid cytokine receptors is increased in the presence of the R1063H when the two mutations are in cis, leading to PV like features in ET. The observed neutrophilia in the double mutation carriers irrespective of cis or trans configuration could be linked to increased granulocyte colony stimulating factor receptor (G-CSFR) signaling, associated with JAK2 V617F/R1063H mutant coupling to G-CSFR with higher affinity than JAK2 V617F alone as demonstrated by co-immunoprecipitation assay.
Permanent Link: http://hdl.handle.net/11104/0294599