Examining disease boundaries: Genetics of myelodysplastic/myeloproliferative neoplasms.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid malignancies that are characterized by dysplasia resulting in cytopenias as well as proliferative features such as thrombocytosis or splenomegaly. Recent studies have better defined the genetics underlying this diverse group of disorders. Trisomy 8, monosomy 7, and loss of Y chromosome are the most common cytogenetic abnormalities seen. Chronic myelomonocytic leukemia (CMML) likely develops from early clones with mutations that drive granulomonocytic differentiation. Mutations in are common and those in the RAS-MAPK pathway are typically implicated in disease with a proliferative phenotype. Several prognostic systems have incorporated genetic features, with most consistently demonstrating worse prognosis. Atypical chronic myeloid leukemia (aCML) is most known for granulocytosis with marked dysplasia and often harbors mutations, but and are more specific to this disease. MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) most commonly involves spliceosome mutations (namely ) and mutations in the JAK-STAT pathway. Finally, MDS/MPN-unclassifiable (MDS/MPN-U) is least characterized but a significant fraction carries mutations in . The remaining patients have clinical and/or genetic features similar to the other MDS/MPNs, suggesting there is room to better characterize this entity. Evolution from age-related clonal hematopoiesis to MDS/MPN likely depends on the order of mutation acquisition and interactions between various biologic factors. Genetics will continue to play a critical role in our understanding of these illnesses and advancing patient care.