Fig. 2: Stem cells maintain the myelodysplastic syndrome phenotype and clonal burden during hypomethylating agent therapy, expand and activate specific survival pathways during blast progression.
a, Frequencies of CMPs and GMPs in the MyHPC compartment of CMP-pattern and GMP-pattern MDS samples, respectively, sequentially collected at baseline (Bsln; n = 15 and n = 21) and during HMA therapy at the times of best response (Resp; n = 10 and n = 8) or no response (N/Resp; n = 7 and n = 15). No significant differences were detected using one-way analysis of variance (ANOVA) with Dunnett’s multiple-comparisons test (CMPs) and a Kruskal–Wallis test with Dunn’s multiple-comparisons test. b, Variant allele frequencies (VAFs) of somatic mutations detected in total BM MNCs and neutrophils (Neutro) from CMP-pattern (left) and GMP-pattern (right) patients with MDS during hematological response to HMAs. c, HSC frequencies in total BM MNCs from MDS samples obtained at baseline (n = 123) and after HMA failure and BP (n = 70). Lines represent medians ± IQRs. Statistical significance was calculated using the two-tailed Mann–Whitney test (****P < 0.0001). d, LT-HSC frequencies in total BM MNCs from CMP-pattern MDS samples obtained at baseline (n = 64) and after HMA failure and BP (n = 30). Lines represent medians ± IQRs. Statistical significance was calculated using the two-tailed Mann–Whitney test (****P < 0.0001). e, LMPP frequencies in total BM MNCs from GMP-pattern MDS samples obtained at baseline (n = 59) and after HMA failure and BP (n = 40). Lines represent medians ± IQRs. Statistical significance was calculated using the two-tailed Mann–Whitney test (****P < 0.0001). f, Gene-set enrichment analysis (GSEA) of genes significantly (P < 0.004) upregulated (top; n = 515) or downregulated (bottom; n = 418) in LT-HSCs isolated from CMP-pattern MDS patients with BP (n = 4) compared with those from patients at baseline (n = 5). Hallmark gene sets with a gene enrichment overlap rate (k/K) > 0.02 and P < 0.01 are shown. EMT, epithelial-mesenchymal transition. g, GSEA of genes significantly (P < 0.01) upregulated (top; n = 352) or downregulated (bottom; n = 164) in LMPPs isolated from GMP-pattern MDS patients with BP (n = 6) compared with those from patients at baseline (n = 6). Hallmark gene sets are shown (P < 0.01; k/K > 0.02).
