A Primer on the Biology of MDS

Abstract

Introduction Myelodysplastic syndromes (MDS) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse.1 In the last decade, genomic technologies coupled with mouse genetic studies have greatly improved our understanding of the genetic elements driving MDS initiation and progression and the ways in which such elements functionally contribute to specific aspects of the disease’s pathobiology.2–6 These studies have revealed that MDS are typically driven by multistep processes that affect a recurrent set of genes, which leads to the clonal expansion of mutant HSCs over their normal counterparts. Disease onset can be accelerated by exposure to cytotoxic chemotherapy, the presence of germ-line predisposition mutations, or any type of stress (e.g., inflammation) that confers a fitness advantage to the mutant clone. Progression from MDS to secondary acute myeloid leukemia (sAML) is mostly associated with the expansion of HSC clones carrying preexisting or newly acquired recurrent mutations affecting hematopoietic transcription factor genes that abrogate normal differentiation or those carrying activating mutations in signaling pathways that control cellular proliferation.7