JAK2V617F mRNA metabolism in myeloproliferative neoplasm cell lines

Nauroy, Pauline; Delhommeau, François; Baklouti, Faouzi

doi:10.1038/bcj.2014.43

Cited by 4 publications

(2 citation statements)

References 13 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our hands, the alternative isoform of JAK2 was also found in MPN patients at a higher level than in healthy controls or patients with reactive thrombocytosis, the highest levels being observed in PMF patients as opposed to other MPN (our unpublished results). In silico analyses predicted that JAK2 V617F mutation led to a switch in the binding affinity between SRSF2 and SRSF6 that may explain exon skipping [ 107 ]. However, in our hands, modification of SRSF2 expression did not alter the skipping of exon 14 on a minigene model, but SRSF6 overexpression did, whether the V617F mutation was present or not (our unpublished results).…”

Section: Consequences Of Splicing Anomalies In Myeloid Malignanciementioning

confidence: 99%

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Hautin

Mornet

Chauveau

et al. 2020

Cancers

View full text Add to dashboard Cite

Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

show abstract

Section: Consequences Of Splicing Anomalies In Myeloid Malignanciementioning

confidence: 99%

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Hautin

Mornet

Chauveau

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…The size of the circles is proportional to the level of significance (only statistically significant correlations are presented, with the p value threshold set as 0.05). Abbreviations: JAK2_ mut_VAF, JAK2 V617F variant allele frequency; JAK2_mut, expression of mutated JAK2 allele; JAK2_wt, expression of wild type JAK2 allele; JAK2_mut_vs_wt, the ratio of expression of mutated JAK2 allele versus wild-type JAK2 allele; JAK2_total, total JAK2 expression (the sum of both alleles); PDL1, expression of PDL1 (CD274) gene; HB, hemoglobin; HCT, hematocrit; PLT, platelets; WBC, white blood count accumulation per JAK2 gene copy, regardless of the presence or absence of the exon 14 JAK2V617F mutation [65].…”

Section: Discussionmentioning

confidence: 99%

Essential thrombocythaemia progression to the fibrotic phase is associated with a decrease in JAK2 and PDL1 levels

et al. 2022

View full text Add to dashboard Cite

It has been postulated that the changes in the molecular characteristics of the malignant clone(s) and the abnormal activation of JAK-STAT signaling are responsible for myeloproliferative neoplasm progression to more advanced disease phases and the immune escape of the malignant clone. The continuous JAK-STAT pathway activation leads to enhanced activity of the promoter of CD274 coding programmed death-1 receptor ligand (PD-L1), increased PD-L1 level, and the immune escape of MPN cells. The aim of study was to evaluate the PDL1 mRNA and JAK2 mRNA level in molecularly defined essential thrombocythaemia (ET) patients (pts) during disease progression to post-ET- myelofibrosis (post-ET-MF). The study group consisted of 162 ET pts, including 30 pts diagnosed with post-ET-MF. The JAK2V617F, CALR, and MPL mutations were found in 59.3%, 19.1%, and 1.2% of pts, respectively. No copy-number alternations of the JAK2, PDL1, and PDCDL1G2 (PDL2) genes were found. The level of PD-L1 was significantly higher in the JAK2V617F than in the JAK2WT, CALR mutation-positive, and triple-negative pts. The PD-L1 mRNA level was weakly correlated with both the JAK2V617F variant allele frequency (VAF), and with the JAK2V617F allele mRNA level. The total JAK2 level in post-ET-MF pts was lower than in ET pts, despite the lack of differences in the JAK2V617F VAF. In addition, the PD-L1 level was lower in post-ET-MF. A detailed analysis has shown that the decrease in JAK2 and PDL1 mRNA levels depended on the bone marrow fibrosis grade. The PDL1 expression showed no differences in relation to the genotype of the JAK2 haplotypeGGCC_46/1, hemoglobin concentration, hematocrit value, leukocyte, and platelet counts. The observed drop of the total JAK2 and PDL1 levels during the ET progression to the post-ET-MF may reflect the changes in the JAK2V617F positive clone proliferative potential and the PD-L1 level–related immunosuppressive effect. The above-mentioned hypothesis is supported by The Cancer Genome Atlas (TCGA) data, confirming a strong positive association between CD274 (encoding PD-L1), CXCR3 (encoding CXCR3), and CSF1 (encoding M-CSF) expression levels, and recently published results documenting a drop in the CXCR3 level and circulating M-CSF in patients with post-ET-MF.

show abstract

The ERK2 DBP domain opposes pathogenesis of a JAK2V617F-driven myeloproliferative neoplasm

Zhang

Truong

Fahl

et al. 2022

Blood

View full text Add to dashboard Cite

While Ras/mitogen-activated protein kinase (MAPK) signaling is activated in most human cancers, attempts to target this pathway using kinase active site inhibitors have not typically led to durable, clinical benefit. To address this shortcoming, we sought to test the feasibility of an alternative targeting strategy, focused on the ERK2 substrate binding domains, D and DBP. We found that disabling the ERK2-DBP domain in mice caused baseline erythrocytosis. Consequently, we investigated the role of the ERK2-D and -DBP domains in disease, using a JAK2-dependent model of polycythemia vera (PV). Importantly, inactivation of the ERK2-DBP domain promoted the progression of disease from PV to myelofibrosis (MF), suggesting that the ERK2-DBP domain normally opposes progression. ERK2-DBP inactivation also prevented oncogenic JAK2 kinase (JAK2V617F) from promoting oncogene-induced senescence (OIS) in vitro. The ERK2-DBP mutation attenuated JAK2-mediated OIS by preventing the physical interaction of ERK2 with the transcription factor, Egr1. Because inactivation of the ERK2-DBP created a functional ERK2 kinase limited to binding substrates through its D-domain, these data suggested that the D-domain substrates were responsible for promoting oncogene-induced progenitor growth and tumor progression, and that pharmacologic targeting of the ERK2-D domain might attenuate cancer cell growth. Indeed, pharmacologic agents targeting the ERK2-D domain were effective in attenuating the growth of JAK2-dependent myeloproliferative neoplasm cell lines. Taken together, these data indicate that the ERK-D and -DBP domains can play distinct roles in the progression of neoplasms and that the D-domain has the potential to be potent therapeutic target in Ras/MAPK dependent cancers.

show abstract

JAK2V617F mRNA metabolism in myeloproliferative neoplasm cell lines

Cited by 4 publications

References 13 publications

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Essential thrombocythaemia progression to the fibrotic phase is associated with a decrease in JAK2 and PDL1 levels

The ERK2 DBP domain opposes pathogenesis of a JAK2V617F-driven myeloproliferative neoplasm

Contact Info

Product

Resources

About