The Impact of Clonal Hierarchy and Heterogeneity on Phenotypic Manifestations of Myelodysplastic Neoplasms

SIMPLE SUMMARY: In this review, we provide a brief account of recent genomic findings, updated guidelines and emerging promising tools to help refine our diagnostic abilities in the setting of myelodysplastic neoplasms; We also discuss limitations of current practices during disease follow-up, to shed light on the pressing need to enhance our prognostic armamentarium in the near future. ABSTRACT: Until recently, conventional prognostication of myelodysplastic neoplasms (MDS) was performed using the revised International Prognostic Scoring System (IPSS-R), with additional adverse prognoses conferred by select mutations. Nonetheless, the clonal diversity and dynamics of coexisting mutations have been shown to alter the prognosis and treatment response in patients with MDS. Often in the process of clonal evolution, various initial hits are preferentially followed by a specific spectrum of secondary alterations, shaping the phenotypic and biologic features of MDS. Our ability to recapitulate the clonal ontology of MDS is a necessary step toward personalized therapy and the conceptualization of a better classification system, which ideally would take into consideration all genomic aberrations and their inferred clonal architecture in individual cases. In this review, we summarize our current understanding of the molecular landscape of MDS and the role of mutational combinations, clonal burden, and clonal hierarchy in defining the clinical fate of the disease.