American Society of Hematology

Figure 3.

$Interpatient and intraclonal DNA methylation heterogeneity. (A) Heatmaps showing pairwise methylation Manhattan distances indicating the level of heterogeneity within each leukemic fraction among all patients. Vertical and horizontal bars indicate the IGHV status of the individual patients. (B) Density histograms of pairwise Pearson correlation coefficients within each leukemic fraction among all patients, separated by IGHV mutational status. Significant differences were observed between U-CLL and M-CLL distributions of correlation coefficients in all fractions (P ≤ 5.174 × 10e-7, Wilcoxon rank sum test with continuity correction). (C) Box plot showing the number of differentially variable CpG sites (DVCs, by DiffVar method) in each of the fractions with significant differences in group variances between U-CLL and M-CLL patients, determined by using all possible permutations of equal number of samples per group (n = 8). (D) Plot of variance and mean methylation levels (β-values) for each CpG site across U-CLL or M-CLL samples. Color lines represent average variance in each subgroup illustrating the higher variance at intermediate β-values and in the M-CLL samples. (E) Box plot showing the distribution of variances for every CpG in the resting (RF) and proliferative (PF) intraclonal fractions, separated by U-CLL (n = 8) and M-CLL (n = 13) classification. Both the Fligner-Killeen test of homogeneity of variances and the paired Wilcoxon signed-rank test were used to compare CpG methylation variances with similar significant results between the paired fractions. ****P < .0001.$

Interpatient and intraclonal DNA methylation heterogeneity. (A) Heatmaps showing pairwise methylation Manhattan distances indicating the level of heterogeneity within each leukemic fraction among all patients. Vertical and horizontal bars indicate the IGHV status of the individual patients. (B) Density histograms of pairwise Pearson correlation coefficients within each leukemic fraction among all patients, separated by IGHV mutational status. Significant differences were observed between U-CLL and M-CLL distributions of correlation coefficients in all fractions (P ≤ 5.174 × 10e-7, Wilcoxon rank sum test with continuity correction). (C) Box plot showing the number of differentially variable CpG sites (DVCs, by DiffVar method) in each of the fractions with significant differences in group variances between U-CLL and M-CLL patients, determined by using all possible permutations of equal number of samples per group (n = 8). (D) Plot of variance and mean methylation levels (β-values) for each CpG site across U-CLL or M-CLL samples. Color lines represent average variance in each subgroup illustrating the higher variance at intermediate β-values and in the M-CLL samples. (E) Box plot showing the distribution of variances for every CpG in the resting (RF) and proliferative (PF) intraclonal fractions, separated by U-CLL (n = 8) and M-CLL (n = 13) classification. Both the Fligner-Killeen test of homogeneity of variances and the paired Wilcoxon signed-rank test were used to compare CpG methylation variances with similar significant results between the paired fractions. ****P < .0001.

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