Genetic complexity of chronic myelomonocytic leukemia

In recent years CMML has received increased attention as the most commonly observed MDS/MPN overlap syndrome. Renewed interest has occurred in part due to widespread adoption of next-generation sequencing panels that help render the diagnosis in the absence of morphologic dysplasia. Although most CMML patients exhibit somatic mutations in epigenetic modifiers, spliceosome components, transcription factors and signal transduction genes, it is increasingly clear that a small subset harbors an inherited predisposition to CMML and other myeloid neoplasms. More intriguing is the fact that the mutational spectrum observed in CMML is found in other types of myeloid leukemias, begging the question of how similar genetic backgrounds can lead to such divergent clinical phenotypes. In this review we present a contemporary snapshot of the genetic complexity inherent to CMML, explore the relationship between genotype-phenotype and present a stepwise model of CMML pathogenesis and progression.