Fig. 4: CTPI2 and complex I inhibitors revert clonal advantage of Dnmt3aR882H/+ LT-HSC.
From: Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
a, Scheme of experimental approach. b, The proportion of CD45.2 cells in PB, normalized to the proportion of injected CD45.2 cells. The mean ± s.e.m. is shown; for Dnmt3aR882H/+ CTPI2, n = 6, for remining groups, n = 5 mice; P by two-sided t-test between Dnmt3aR882H/+ vehicle and Dnmt3aR882H/+ CTPI2 is shown. c, The proportion of transplanted cells in LT-HSC by flow cytometry at week 16. One sample per group is shown; similar results were observed for n = 5. d, Frequencies of CD45.2-LT-HSC in BM at week 16, normalized to the proportion of injected LT-HSC. The mean ± s.e.m. is shown; for Dnmt3aR882H/+ CTPI2, n = 6 mice, for remining groups, n = 5 mice. e, Schematic summary of the experimental approach. HSPCs isolated 12 weeks post-transplant were plated in semisolid media with 100 nM IACS-010759/vehicle for seven days. f, Quantified colonies; the mean ± s.d. is shown; n = 3 mice per group. g, Schema of experimental approach for IACS-010759/vehicle treatment. h, Frequencies of CD45.2 LT-HSC in mouse BM at endpoint. The mean ± s.e.m. is shown; n = 5 mice for both vehicle groups, and n = 6 for both IACS-010759 groups. i, Schematic representation of metformin treatment model. Dnmt3aR882H/+ were mixed with WT BM cells in 1:2 proportion and transplanted into lethally irradiated recipient mice. Metformin (125 mg kg−1) or vehicle treatment started from week 5 for six weeks. j, Frequencies of transplanted Dnmt3aR882H/+ and WT LT-HSC in BM; the mean ± s.d. is shown; n = 3 mice for vehicle group, and n = 6 mice per metformin group. P in d, f, h, j by one-way ANOVA with Tukey correction. Schematics in a,e,g,i were created using BioRender (https://biorender.com).
