Exome sequencing studies in chronic myelomonocytic leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of recurrent gene mutations in ASXL1, SRSF2, and TET2, each approaching 40% in incidence. This has led to the clinical implementation of next-generation sequencing panels that effectively identify clonal monocytosis and complement clinical prognostic scoring systems in most patients. However, most murine models based on single gene mutations fail to recapitulate the CMML phenotype, and many gene mutations are loss of function, making the identification of traditional therapeutic vulnerabilities challenging. Further, as a subtype of the myelodysplastic/myeloproliferative neoplasms, CMML has a complex clinical heterogeneity not reflected by the mutational landscape. In this review, we will discuss the discordance between mutational homogeneity and clinical complexity and highlight novel genomic and nongenomic approaches that offer insight into the underlying clinical characteristics of CMML.
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