Figure 2.
DNMT3A-mutated clones enriched in FDs expand in EPO-induced stress, whereas preleukemic R882-mutant clones expand in IFN-γ–induced stress. (A) Schematic representation of genetic engineering of human HSCs to introduce mutations found in frequent blood donors and perform long-term culture (LTC) in the presence of different stimuli over 4 weeks. VAF between conditions was compared at the end of the coculture at 4 weeks. (B) For each DNMT3A mutant clone from FD, a significant increase of the VAF was observed when comparing nontreated (CTRL) and EPO conditions after 4 weeks in culture. Each dot represents an independent biological donor. Paired t test for each biological donor between different conditions was used for statistical significance. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. (C) Fold change expansion under different conditions of each mutation in all CB donors tested (n = 4-13). For clone W305∗, S663fs, and clone E733∗, 13 biological donors were tested over 4 independent experiments. For clones R882H and R882C, 4 to 7 biological donors were tested in 2 independent experiments. Each dot represents an independent biological donor. t test for each biological donor between different conditions was used for statistical significance of the percentage of the DNMT3A-mutant clones. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. See supplemental Figure 3F for results obtained with BM-derived HSCs. CB, cord blood; CTRL, control; FC, fold change; FDC, frequent donor cohort.

DNMT3A-mutated clones enriched in FDs expand in EPO-induced stress, whereas preleukemic R882-mutant clones expand in IFN-γ–induced stress. (A) Schematic representation of genetic engineering of human HSCs to introduce mutations found in frequent blood donors and perform long-term culture (LTC) in the presence of different stimuli over 4 weeks. VAF between conditions was compared at the end of the coculture at 4 weeks. (B) For each DNMT3A mutant clone from FD, a significant increase of the VAF was observed when comparing nontreated (CTRL) and EPO conditions after 4 weeks in culture. Each dot represents an independent biological donor. Paired t test for each biological donor between different conditions was used for statistical significance. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. (C) Fold change expansion under different conditions of each mutation in all CB donors tested (n = 4-13). For clone W305∗, S663fs, and clone E733∗, 13 biological donors were tested over 4 independent experiments. For clones R882H and R882C, 4 to 7 biological donors were tested in 2 independent experiments. Each dot represents an independent biological donor. t test for each biological donor between different conditions was used for statistical significance of the percentage of the DNMT3A-mutant clones. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. See supplemental Figure 3F for results obtained with BM-derived HSCs. CB, cord blood; CTRL, control; FC, fold change; FDC, frequent donor cohort.

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