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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F18%3A73590410" target="_blank" >RIV/61989592:15110/18:73590410 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/18:00502682 RIV/00023736:_____/18:00012484

Výsledek na webu

<a href="http://www.bloodjournal.org/content/bloodjournal/132/25/2695.full.pdf" target="_blank" >http://www.bloodjournal.org/content/bloodjournal/132/25/2695.full.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood-2018-04-843060" target="_blank" >10.1182/blood-2018-04-843060</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Clinical consequences of driver mutations in myeloproliferative neoplasms (MPNs) are well established, yet little is known about the impact of co-occurring JAK2 variants on the phenotype of MPNs. We tested a cohort of 390 JAK2 V617F-positive MPN patients for JAK2 R1063H, a variant previously described in polycythemia vera and hereditary erythrocytosis. We identified 14 carriers of both JAK2 V617F and JAK2 R1063H mutations. These patients exhibited significantly higher rate of neutrophilic granulocytosis compared to those harboring JAK2 V617F only. 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 other patients with high JAK2 V617F allelic burden, the JAK2 R1063H was nearly homozygous (&gt;80%), suggesting the acquisition of the second allele by uniparental disomy. In 3 patients the R1063H mutation was acquired (allele percentage between 20.7% - 31.5%). Our functional studies demonstrated that the JAK2 V617F-induced signaling via the dimeric myeloid cytokine receptors is increased in the presence of the R1063H when the two mutations are in cis. Thus, acquisition of V617F in cis on a germline R1063H allele, or an acquisition of additional R1063H mutation increases JAK2 V617F oncogenic signaling that promotes neutrophilia.

Název v anglickém jazyce

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

Popis výsledku anglicky

Clinical consequences of driver mutations in myeloproliferative neoplasms (MPNs) are well established, yet little is known about the impact of co-occurring JAK2 variants on the phenotype of MPNs. We tested a cohort of 390 JAK2 V617F-positive MPN patients for JAK2 R1063H, a variant previously described in polycythemia vera and hereditary erythrocytosis. We identified 14 carriers of both JAK2 V617F and JAK2 R1063H mutations. These patients exhibited significantly higher rate of neutrophilic granulocytosis compared to those harboring JAK2 V617F only. 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 other patients with high JAK2 V617F allelic burden, the JAK2 R1063H was nearly homozygous (&gt;80%), suggesting the acquisition of the second allele by uniparental disomy. In 3 patients the R1063H mutation was acquired (allele percentage between 20.7% - 31.5%). Our functional studies demonstrated that the JAK2 V617F-induced signaling via the dimeric myeloid cytokine receptors is increased in the presence of the R1063H when the two mutations are in cis. Thus, acquisition of V617F in cis on a germline R1063H allele, or an acquisition of additional R1063H mutation increases JAK2 V617F oncogenic signaling that promotes neutrophilia.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BLOOD

ISSN

0006-4971

e-ISSN

—

Svazek periodika

132

Číslo periodika v rámci svazku

25

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

2695-2699

Kód UT WoS článku

000453926500012

EID výsledku v databázi Scopus

2-s2.0-85058788204