Human myeloid malignancies with ASXL1/EZH2 and lymphoid CLL with ASXL1 mutations show reactivation of L1 TEs and are sensitive to P treatment. (A) Wald statistics are shown for L1 TEs for a comparison between human MDS BM samples with ASXL1/EZH2 (n = 3) mutations and human MDS BM samples with other mutations (n = 109). (B) GSVA was performed on the whole human MDS BM data set (n = 112) and mean values for ASXL1/EZH2 mutant samples and samples with other mutations are shown in the heat map for DNA repair-related gene sets. (C) The relative number of cells for the indicated patient samples in indicated treatment groups are shown. MDS A/Emut, n = 4; MLLr, n = 2. (D) The bar charts (left) show the percentage of cells with ≥10 γH2AX foci after the indicated treatment for MDS A/Emut. Representative images (right) of γH2AX foci (green) and their merge with DAPI (blue) for the indicated treatments are shown. (E) Comet assay was performed after the indicated treatment on MDS A/Emut and MLLr cells and head length, tail length, and tail moment are shown in the violin plots (left). Example pictures for C and other treatments for the indicated cell types are shown (right). (F) Wald statistics are shown for L1 TEs for a comparison between human CLL samples with ASXL1 (n = 5) mutations and human CLL with other mutations (n = 161). (G) GSVA was performed on the whole human CLL data set (n = 166) and mean values for ASXL mutant samples and samples with other mutations are shown in the heat map for DNA repair-related gene sets. (H) The relative number of B cells of human CLL samples with the indicated mutations (n = 5 each) is shown after in vitro culture with or without P. (I) The fold increase in number of cells with ≥10 γH2AX foci is shown for the indicated human CLL cells with or without P treatment. (J) Comet assay was performed after the indicated treatment on human ASXL1-mutated CLL cells and head length, tail length, and tail moment are shown in the bar charts (top). Example pictures are shown (below). (K) The relative number of B cells of human CLL samples with ASXL1 mutations is shown with or without the indicated treatments (n = 4). Plots show mean ± SEM, ∗P < .05, ∗∗P < .01, ∗∗∗P < .001, ∗∗∗∗P < .001, unpaired t test. C, control; L1, LINE1; MDS A/Emut, human ASXL1/EZH2-mutated MDS cells; MLLr, MLL-rearranged AML; P, PARPi; P+D, PARPi + didanosine.

Human myeloid malignancies with ASXL1/EZH2 and lymphoid CLL with ASXL1 mutations show reactivation of L1 TEs and are sensitive to P treatment. (A) Wald statistics are shown for L1 TEs for a comparison between human MDS BM samples with ASXL1/EZH2 (n = 3) mutations and human MDS BM samples with other mutations (n = 109). (B) GSVA was performed on the whole human MDS BM data set (n = 112) and mean values for ASXL1/EZH2 mutant samples and samples with other mutations are shown in the heat map for DNA repair-related gene sets. (C) The relative number of cells for the indicated patient samples in indicated treatment groups are shown. MDS A/Emut, n = 4; MLLr, n = 2. (D) The bar charts (left) show the percentage of cells with ≥10 γH2AX foci after the indicated treatment for MDS A/Emut. Representative images (right) of γH2AX foci (green) and their merge with DAPI (blue) for the indicated treatments are shown. (E) Comet assay was performed after the indicated treatment on MDS A/Emut and MLLr cells and head length, tail length, and tail moment are shown in the violin plots (left). Example pictures for C and other treatments for the indicated cell types are shown (right). (F) Wald statistics are shown for L1 TEs for a comparison between human CLL samples with ASXL1 (n = 5) mutations and human CLL with other mutations (n = 161). (G) GSVA was performed on the whole human CLL data set (n = 166) and mean values for ASXL mutant samples and samples with other mutations are shown in the heat map for DNA repair-related gene sets. (H) The relative number of B cells of human CLL samples with the indicated mutations (n = 5 each) is shown after in vitro culture with or without P. (I) The fold increase in number of cells with ≥10 γH2AX foci is shown for the indicated human CLL cells with or without P treatment. (J) Comet assay was performed after the indicated treatment on human ASXL1-mutated CLL cells and head length, tail length, and tail moment are shown in the bar charts (top). Example pictures are shown (below). (K) The relative number of B cells of human CLL samples with ASXL1 mutations is shown with or without the indicated treatments (n = 4). Plots show mean ± SEM, ∗P < .05, ∗∗P < .01, ∗∗∗P < .001, ∗∗∗∗P < .001, unpaired t test. C, control; L1, LINE1; MDS A/Emut, human ASXL1/EZH2-mutated MDS cells; MLLr, MLL-rearranged AML; P, PARPi; P+D, PARPi + didanosine.

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