Fig. 2. Alterations in driver mutation profiles delineate stages of CMML progression. Whole exome analysis of 48 paired CMML and secondary AML (sAML) samples.
A Prevalence of driver mutations and somatic copy number alterations (SCNAs) in CMML and sAML. RAS pathway represents all mutations in MAPK pathway. B Frequency of driver mutations and SCNAs in CMML and sAML. C Violin plots depicting variant allele frequencies (VAFs) for the most frequent driver mutations in CMML and sAML. D Frequency of driver mutations and SCNAs in CMML and sAML and their categorization as 1d, 2d, or 3d. E Genetic profiling of CMML evolution in eighteen patients at two time points by whole exome sequencing. F Odds ratios of genetic factors selected by the L1-regularized logistic regressions that have the greatest impact on dysplastic/proliferative CMML categorization and leukemic transformation (LT) risk. The x-axis represents odds ratios of LT risk (high or low). The y-axis represents categorization of low or high white blood cell (WBC) count, or pCMML vs dCMML classification. The horizontal and vertical size of ellipses reflects corresponding p-values calculated by two-tailed Fisher’s exact test. Additionally, confidence intervals (ɑ = 0.05) of odds ratio values are presented. The mean is the measure of center. G Stratification of parameters associated with aggressive disease phenotype by number of driver mutations. H Fish plots derived from patient-derived single colony assays of representative cases of pCMML (left) and dCMML (right). Scatter plot to the left of each fish plot represents the genotype of individual colonies as determined by Sanger sequencing of the indicated genes. RAS mutation status is depicted on the x-axis. The arrow indicates inferred evolutionary trajectory from which the fish plot was derived.