Impact of Epigenetic Mutations in Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm that is characterized by sustained monocytic proliferation, bone marrow dysplasia, and progression to acute myeloid leukemia (AML). Somatic mutations are observed in most patients, with mutations in epigenetic regulatory genes being frequent and often impacting survival outcomes. Deeper understanding of the biological impacts of these mutations has resulted in rationally derived precision therapeutics. Here, we discuss two classes of epigenetic regulator genes and describe the prevalence and impact of somatic mutations in these genes on CMML outcomes.

The increased use and availability of sequencing techniques in the clinical setting has demonstrated the prevalence of mutations in epigenetic regulator genes in CMML. This has provided additional cases to study the impact of these mutations on survival outcomes, leading to the incorporation of some of these mutations in contemporary molecular CMML prognostic models (ASXL1, TET2). Furthermore, advances in understanding epigenetic dysregulation in CMML have led to the development of emerging targeted therapies for select patients. Studying the prevalence of these mutations and their biological implications in CMML may offer an opportunity to identify genotypes likely to respond to treatment or to develop targeted mutation-specific therapies.