17 research outputs found
A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia
Sampling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12;21) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis
In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis
Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) is an autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML. Mutation analyses of RUNX1 in 3 families with FPD/AML showing linkage to chromosome 21q22.1 revealed 3 novel heterozygous point mutations (K83E, R135fsX177 (IVS4 + 3delA), and Y260X). Functional investigations of the 7 FPD/AML RUNX1 Runt domain point mutations described to date (2 frameshift, 2 nonsense, and 3 missense mutations) were performed. Consistent with the position of the mutations in the Runt domain at the RUNX1-DNA interface, DNA binding of all mutant RUNX1 proteins was absent or significantly decreased. In general, missense and nonsense RUNX1 proteins retained the ability to heterodimerize with PEBP2beta/CBFbeta and inhibited transactivation of a reporter gene by wild-type RUNX1. Colocalization of mutant RUNX1 and PEBP2beta/CBFbeta in the cytoplasm was observed. These results suggest that the sequestration of PEBP2beta/CBFbeta by mutant RUNX1 may cause the inhibitory effects. While haploinsufficiency of RUNX1 causes FPD/AML in some families (deletions and frameshifts), mutant RUNX1 proteins (missense and nonsense) may also inhibit wild-type RUNX1, possibly creating a higher propensity to develop leukemia. This is consistent with the hypothesis that a second mutation has to occur, either in RUNX1 or another gene, to cause leukemia among individuals harboring RUNX1 FPD/AML mutations and that the propensity to acquire these additional mutations is determined, at least partially, by the initial RUNX1 mutation
R-Spondin Potentiates Wnt/b-Catenin Signaling Through Orphan Receptors LGR4 and LGR5
The Wnt/b-catenin signaling pathway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/b-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced b-catenin signaling. From this screen, we identified LGR4, then an orphan G protein-coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced b-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated b-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4-/- crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications
High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder
Working With Parents of Gender-Variant Children: Using Social Action as an Emancipatory Research Framework
RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML
Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey
We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2–30) and 7 (range 2–25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.</p