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• W4313148439 abstract "Age related clonal haematopoiesis (ARCH) results from clonal expansion of hematopoietic stem cells (HSCs), driven by recurrent leukemic mutations, and carries an increased risk of haematological malignancies and cardiometabolic disease. DNMT3A R882 is the most common ARCH mutation, and we hypothesise that it affects the differentiation dynamics of HSCs, potentially contributing to disease risk. To comprehensively characterise changes in HSC differentiation driven by DNMT3A R882 at single cell resolution, 2785 single phenotypic HSC/MPPs (CD33-/CD34+/CD45dim/CD38-/CD45RA-) from 6 individuals were cultured in media supporting differentiation into all major blood lineages. DNMT3A R882 HSC derived colonies were compared with WT colonies within each individual. Outcomes were analysed using flow phenotyping combined with novel multiparameter in silico analysis pipelines, targeted genotyping and for one sample RNA-seq and whole genome sequencing followed by phylogenetic analysis based on somatic mutations. The number of HSCs committing to the erythroid, myeloid or lymphoid (NK) lineages were similar between DNMT3A R882 and WT HSCs. DNMT3A R882 HSCs however, produced more mature granulocytes and fewer mature monocytes than WT HSCs (as measured by proportions and MFI of CD14+, CD15+ & CD66b+ cells in mature colonies). Transcriptional profiles from RNAseq of monocytic colonies confirmed the presence of less mature monocytes in DNMT3A R882 colonies compared to WT in one ARCH sample. Overall, our data indicate that DNMT3A R882 mutation in HSCs alters monocyte and neutrophil differentiation dynamics. We speculate these defects respectively contribute to the early changes that may lead to phenotypic AML following secondary somatic mutations; and increased risk of cardiovascular disease observed in DNMT3A R882 carriers, for which clear mechanisms have not been identified to date. Age related clonal haematopoiesis (ARCH) results from clonal expansion of hematopoietic stem cells (HSCs), driven by recurrent leukemic mutations, and carries an increased risk of haematological malignancies and cardiometabolic disease. DNMT3A R882 is the most common ARCH mutation, and we hypothesise that it affects the differentiation dynamics of HSCs, potentially contributing to disease risk. To comprehensively characterise changes in HSC differentiation driven by DNMT3A R882 at single cell resolution, 2785 single phenotypic HSC/MPPs (CD33-/CD34+/CD45dim/CD38-/CD45RA-) from 6 individuals were cultured in media supporting differentiation into all major blood lineages. DNMT3A R882 HSC derived colonies were compared with WT colonies within each individual. Outcomes were analysed using flow phenotyping combined with novel multiparameter in silico analysis pipelines, targeted genotyping and for one sample RNA-seq and whole genome sequencing followed by phylogenetic analysis based on somatic mutations. The number of HSCs committing to the erythroid, myeloid or lymphoid (NK) lineages were similar between DNMT3A R882 and WT HSCs. DNMT3A R882 HSCs however, produced more mature granulocytes and fewer mature monocytes than WT HSCs (as measured by proportions and MFI of CD14+, CD15+ & CD66b+ cells in mature colonies). Transcriptional profiles from RNAseq of monocytic colonies confirmed the presence of less mature monocytes in DNMT3A R882 colonies compared to WT in one ARCH sample. Overall, our data indicate that DNMT3A R882 mutation in HSCs alters monocyte and neutrophil differentiation dynamics. We speculate these defects respectively contribute to the early changes that may lead to phenotypic AML following secondary somatic mutations; and increased risk of cardiovascular disease observed in DNMT3A R882 carriers, for which clear mechanisms have not been identified to date." @default.
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• W4313148439 date "2022-01-01" @default.
• W4313148439 modified "2023-09-29" @default.
• W4313148439 title "3214 – DNMT3A R882 MUTATION IN HUMAN HAEMATOPOIETIC STEM CELLS ALTERS DIFFERENTIATION TOWARDS NEUTROPHILS AND MONOCYTES" @default.
• W4313148439 doi "https://doi.org/10.1016/j.exphem.2022.07.270" @default.
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