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DNMT3A CHIP-driver mutations IGNITE the bone marrow

2023; Elsevier BV; Volume: 379; Linguagem: Inglês

10.1016/j.atherosclerosis.2023.06.936

1879-1484

Tsai-Sang Dederichs, Carolin A. Ehlert, Heiko Becker, Dietmar Pfeifer, Christoph Niemoeller, Nathaly Anto-Michel, Andreas Zirlik, Christoph Bode, Dennis Wolf, Constantin von zur Mühlen, Klaus Kaier, Sebastian Preißl, Timo Heidt, Dirk Westermann, Ingo Hilgendorf,

Blood disorders and treatments

Background and Aims: The study aimed to identify phenotypical changes directly attributed to DNMT3A-CHIP driver mutations in blood and bone marrow myeloid cells from patients with coronary artery disease risk. Methods: We conducted a prospective, observational study to screen CHIP-driver mutations in patients who were admitted for percutaneous coronary intervention. We established a single-cell DNA/RNA parallel sequencing method to acquire whole transcriptome and DNMT3A genotype of the same single blood monocytes from four DNMT3A mutation carriers and three matched non-carriers. We also applied such parallel sequencing method to bone marrow stem and progenitor cells from one DNMT3Ahotspot mutation carrier, who underwent sternotomy. Results: One third of patients in our cohort (53 out of 178) harbored CHIP-driver mutations with DNMT3A and TET2 accounting for 83% of the mutated CHIP genes. Middle-aged DNMT3A or TET2 carriers presented higher severity of coronary artery stenosis than the non-carriers. A total of 1268 blood monocytes were profiled with the parallel sequencing method, whereby we revealed that monocytes from DNMT3A mutation carriers upregulated pro-inflammatory markers, such as the S100A8 and S100A9 alarmins, in comparison with those from the non-carriers. Intra-individual comparison of approximately 100 mutant and 100 non-mutant monocytes of each carrier manifested an identical transcriptome profile, whereas the mutant hematopoietic stem and progenitor cells upregulated secretory cytokines, such as IL-1B and HMGB1, as opposed to their non-mutant counterparts. Conclusions: Few bone marrow progenitor cells carrying DNMT3A-CHIP driver mutations suffice to induce proatherogenic inflammation in all monocytes –mutant and non-mutant ones alike.