Publications by authors named "Mira Khoury"
Background: Pregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation.
Methods: We studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2.
Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.
View Article and Find Full Text PDFInferring the initiation and development of myeloproliferative neoplasms.
Proc Natl Acad Sci U S A
September 2022
Article Synopsis
- Blood cancer development starts with mutations and the growth of malignant cell clones, primarily occurring in hematopoietic stem cells that are hard to study directly in living organisms.
- We suggest using mathematical modeling and statistical methods to analyze how the disease begins and progresses over time, which can help overcome observational challenges.
- Our research indicates that mutations usually appear later in life and highlights the faster growth rate of malignant clones, showing how these techniques can aid in creating early screening strategies.
Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPOR ) in a large family diagnosed with JAK2 -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2 clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells.
View Article and Find Full Text PDFArticle Synopsis
- Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are disorders caused by mutations in specific genes, primarily affecting hematopoietic stem cells.
- Interferon α (IFNα) has shown potential in inducing remission for MPN patients, and a study involving 48 patients over 5 years assessed its long-term effectiveness by analyzing cell mutations.
- Findings suggest that IFNα is more effective in treating homozygous JAK2V617F mutations and that molecular responses vary with different mutations and dosages of IFNα, indicating a mechanism of HSC exhaustion.
Article Synopsis
- Mutations in the calreticulin (CALR) gene are found in around 30% of patients with essential thrombocythemia and primary myelofibrosis, contributing to the development of myeloproliferative neoplasms (MPNs).
- Researchers utilized induced pluripotent stem cell (iPSC) technology to model CALR gene mutations and created several iPSC clones from CD34 progenitors taken from four patients.
- The study revealed that CALRdel52 promotes a greater increase in progenitor cells compared to CALRins5, both mutations enable megakaryocyte expansion, and indicate a potential for new treatment strategies targeting these specific CALR mutations in MPNs.
EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation.
View Article and Find Full Text PDFArticle Synopsis
- - The study examines how mutations in calreticulin (CALRm) impact patients with essential thrombocythemia and myelofibrosis, showing that these mutations primarily affect blood cells and lead to early clonal dominance in hematopoietic stem and progenitor cells (HSPC).
- - Type 1 CALRm spreads more easily in lymphoid cells than type 2 CALRm and is linked to a greater increase in various blood progenitors, while both types increase megakaryocytic progenitors and show different effects on signaling pathways.
- - Results indicate that CALRm mutations serve as both initial and phenotypic events in the disease progression, with type 1 CALRm exhibiting a stronger influence on blood
Background: Epidural fentanyl is commonly used for initiation of early labor analgesia. The aim of this prospective study is to test the hypothesis that duration of epidural fentanyl analgesia differs in nulliparous women requesting epidural analgesia in early labor who are variant allele carriers of the OPRM1 SNVs 118A>G rs1799971, IVS2+31G>A rs9479757, and IVS2+691G>C rs2075572.
Methods: Two hundred and twenty parturients who received epidural analgesia with fentanyl were included in the 118A>G analysis, and a 196 sub-cohort was included in the IVS2+31G>A and IVS2+691G>C exploratory analysis.
Mutations in the calreticulin gene (CALR) represented by deletions and insertions in exon 9 inducing a -1/+2 frameshift are associated with a significant fraction of myeloproliferative neoplasms (MPNs). The mechanisms by which CALR mutants induce MPN are unknown. Here, we show by transcriptional, proliferation, biochemical, and primary cell assays that the pathogenic CALR mutants specifically activate the thrombopoietin receptor (TpoR/MPL).
View Article and Find Full Text PDFArticle Synopsis
- Frameshift mutations in the CALR gene are found in about 30% of patients with essential thrombocythemia and myelofibrosis, leading to increased platelet production.
- In experiments using mice, CALRdel52 (type I) and CALRins5 (type II) mutations caused significant megakaryocyte hyperplasia and were capable of transmitting the disease to secondary recipients, with CALRdel52 leading to myelofibrosis and splenomegaly after 6 months.
- The study highlighted that CALR mutants activate the thrombopoietin receptor (MPL), which is essential for inducing thrombocytosis, while a specific deleted mutant (CALRdelex9) did not cause disease
Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects.
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