Fig. 4: Venetoclax-based-therapy selectively targets hematopoietic stem cells from common myeloid progenitor-pattern myelodysplastic syndrome at blast progression after hypomethylating agent therapy failure.
a, Cumulative time to achieve CR in CMP-pattern (n = 8) and GMP-pattern (n = 13) MDS patients with BP after HMA therapy failure treated with venetoclax-based therapy. Statistical significance was calculated using the log-rank (Mantel–Cox) test (P = 0.018). b, BM MNC frequencies of immunophenotypic LT-HSCs from CMP-pattern MDS patients with BP (left), and LT-HSCs and LMPPs from GMP-pattern MDS patients with BP (center and right). Sequential samples were analyzed before the start of venetoclax-based therapy (C0, cycle 0; n = 8 and n = 8, respectively) and at the time of hematological remission (CR/mCR, complete remission or marrow CR; n = 5 and n = 4, respectively). Lines represent means ± IQRs. Statistical significance was determined using two-tailed Mann–Whitney tests (*P = 0.045). c, t-SNE plots of mass cytometry data displaying 287,354 and 509,697 BM MNCs isolated from a representative patient with CMP-pattern MDS (top) and one patient with GMP-pattern MDS (bottom), respectively, at multiple time points during therapy. Each dot represents one cell. Different colors indicate the hematopoietic clusters (left) and sample origin of each cell (right). Er, erythroid; Prog, progenitors; DCs, dendritic cells; Lymph, lymphoid; DP, double positive (CD4+CD8+); NK, natural killer; SD, stable disease (SD 1, after 1 cycle of therapy; SD 2, after 2 cycles of therapy); mCR, marrow complete remission; C0, cycle zero; PD, progressive disease. d, Frequencies of CD34+ HSPCs in the total BM MNC samples from the patients with CMP-pattern MDS (left) and GMP-pattern MDS (right) shown in c, at the indicated time points (n = 1 sample per time point). e, Metascape pathway enrichment analysis of the marker genes of cluster 1 (LMPPs) shown in Supplementary Fig. 11 (adjusted P value ≤ 0.05; n = 1,722 genes). The top ten Hallmark gene sets are shown. IFN-γ, interferon gamma.
