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

Mambet, Cristina; Babošová, Oľga; Defour, Jean‐Philippe; Leroy, Emilie; Necula, Laura; Stanca, Oana; Tatic, Aurelia; Berbec, Nicoleta; Coriu, Daniel; Beličková, Monika; Kralova, Barbora; Lanikova, Lucie; Veselá, Jitka; Pecquet, Christian; Saussoy, Pascale; Havelange, Violaine; Diaconu, Carmen C.; Divoký, Vladimír; Constantinescu, Stefan N.

doi:10.1182/blood-2018-04-843060

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…Indeed, JAK2 levels are regulated through proteasome-mediated degradation, and the V617F mutation is associated with a higher degradation rate [ 36 ]. Consistently, lower amounts of JAK2 with V617F in comparison with the wild-type form were previously observed in HEK293T cells transfected with JAK2 mutants, despite higher levels of phosphorylated (active) JAK2 [ 14 ]. Altogether, these findings indicate that JAK2 mutation may not have a large impact on protein signaling in cells with regulated total JAK2 levels.…”

Section: Discussionsupporting

confidence: 83%

“…By themselves, these germline mutations usually do not induce substantial changes in JAK2 activity. However, they may augment the effect of V617F on JAK2 signaling in MPN, as described for the R1063H mutation [ 10 , 14 ] or for the germline T108A [ 15 ]. Germline JAK2 mutations can be clinically silent or lead to slight elevations in blood counts (erythrocytes, platelets) or increments in thrombotic risk.…”

Section: Introductionmentioning

confidence: 99%

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A novel germline hyperactivating JAK2 mutation L604F

Dvořáček,

Marková,

Holoubek

et al. 2023

Ann Hematol

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Somatic JAK2 mutations are the main molecular cause of the vast majority of polycythemia vera (PV) cases. According to a recent structural model, the prevalent acquired V617F mutation improves the stability of the JAK2 dimer, thereby enhancing the constitutive JAK2 kinase activity. Germline JAK2 mutations usually do not largely alter JAK2 signaling, although they may modulate the impact of V617F. We found an unusual germline JAK2 mutation L604F in homozygous form in a young PV patient, along with a low allele burden JAK2 V617F mutation, and in her apparently healthy sister. Their father with a PV-like disease had L604F in a heterozygous state, without V617F. The functional consequences of JAK2 L604Fmutation were compared with those induced by V617F in two different in vitro model systems: (i) HEK293T cells were transfected with plasmids for exogenous JAK2-GFP expression, and (ii) endogenous JAK2 modifications were introduced into HeLa cells using CRISPR/Cas9. Both mutations significantly increased JAK2 constitutive activity in transfected HEK293T cells. In the second model, JAK2 modification resulted in reduced total JAK2 protein levels. An important difference was also detected: as described previously, the effect of V617F on JAK2 kinase activity was abrogated in the absence of the aromatic residue F595. In contrast, JAK2 hyperactivation by L604F was only partially inhibited by the F595 change to alanine. We propose that the L604F mutation increases the probability of spontaneous JAK2 dimer formation, which is physiologically mediated by F595. In addition, L604F may contribute to dimer stabilization similarly to V617F.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

A novel germline hyperactivating JAK2 mutation L604F

Dvořáček,

Marková,

Holoubek

et al. 2023

Ann Hematol

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“…A growing body of literature is highlighting the potential clinical significance of this germline variant in the MPN setting. Indeed, JAK2R1063H weakly hyperactivates JAK2/ STAT5 signaling as compared to the acquired somatic V617F, but likely cooperates with another germline variant, JAK2E846D, in hereditary erythrocytosis (25) and with JAK2V617F itself in MPNs, favoring a more aggressive disease phenotype with significantly higher neutrophil counts and enrichment in thrombotic events (26). A potential pro-thrombotic role of this variant is further supported by a whole-exome sequencing study conducted in 22 young ischemic stroke patients with familial clustering of stroke, in which JAK2R1063H was detected in a proband with embolic stroke of undetermined source and prothrombotic status (27).…”

Section: Discussionmentioning

confidence: 99%

Morphological, clinical, and molecular profiling of post-polycythemia vera accelerated/blast phase occurring with and without antecedent secondary myelofibrosis

Pelagatti,

Pozzi,

Cortellazzi

et al. 2024

Front. Hematol.

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IntroductionPolycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and an intrinsic risk of transformation into acute myeloid leukemia (AML), known as blast-phase (BP) disease, a condition typified by dismal prognosis. In PV, the evolution to BP generally occurs through an overt fibrotic progression, represented by the post-PV myelofibrotic (MF) stage. However, direct leukemic transformation from PV may also occur in up to ~50% of patients. In this study, we sought to shed light on the morphological, clinical, and molecular features that may differentiate BP arising from a direct transition from the PV stage (post-PV-BP) from those evolving through a diagnosis of post-PV myelofibrosis (post-PV-MF-BP). Methods and resultsWe retrospectively analyzed a cohort of post-PV-BP (n=5) and post-PV-MF-BP (n=5). We found that BP arising from PV directly displayed significantly lower leukocyte count (median 2.93 × 109/L, range: 2.30–39.40 vs. median 41.05 × 109/L, range: 5.46–58.01; P=0.03), and spleen diameter (14.0 cm, range: 11.5–20.0 vs. 25.5 cm, range: 18–26; P=0.03) as compared to those experiencing an overt fibrotic stage. The most striking differences emerged from bone marrow (BM) morphological analysis: all post-PV-BP were characterized by significantly higher cellularity (median 70%, range: 60%–98% vs. 28%, range: 2%–41%, P=0.0245), lower degree of fibrosis (fibrosis grade 1 vs. fibrosis grade 3 in all cases, P=0.008) and dysplastic features involving all three lineages, most prominently the erythroid and megakaryocytic compartment. Next-generation sequencing (NGS) analysis revealed that post-PV-BP cases were enriched in mutations located in genes involved in DNA methylation such as DNMT3A, IDH1/2, and TET2 (45% vs. 15%, P=0.038). DiscussionWith all the limits of the small number of patients for each cohort, our data suggest that BPs that arise directly from PV present a peculiar phenotype, consistent with the molecular signature of the disease, typified by mutations of genes occurring with a high frequency in Myelodysplastic Syndromes (MDS) and MDS/MPN. Further studies in larger cohorts are warranted to translate these observations into robust evidence that may advise therapeutic choices.

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“…The germline JAK2 mutations were identified both in the pseudokinase (V617I, R564Q S755R) and in the kinase (R867Q, R938Q) domain [19,20,21], giving rise to the thrombocytosis phenotype. In some cases, the germline JAK2 mutations were found to co-exist with JAK2 V617F, further enhancing its signaling and likely predisposing the progenitor cells to the acquisition of JAK2 V617F [22,23]. Further, two germline JAK2 mutations, E846D and R1063H, were described in a case of hereditary erythrocytosis accompanied by megakaryocytic atypia [24], with R1063H being initially described in three out of 93 PV patients that were positive for JAK2 V617F [17].…”

Section: Mutational Landscape Of Mpnmentioning

confidence: 99%

Experimental Modeling of Myeloproliferative Neoplasms

Lanikova

Babošová

Prchal

2019

Genes

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Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.

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

Cited by 5 publications

References 15 publications

A novel germline hyperactivating JAK2 mutation L604F

A novel germline hyperactivating JAK2 mutation L604F

Morphological, clinical, and molecular profiling of post-polycythemia vera accelerated/blast phase occurring with and without antecedent secondary myelofibrosis

Experimental Modeling of Myeloproliferative Neoplasms

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