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Hematologic Malignancies Editorial Myelodysplastic Syndromes—Just a Matter of Age? Carolien M Woolthuis 1 and Christopher Y Park 1,2 1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, US; 2. Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, US Abstract The myelodysplastic syndromes (MDS) are primarily a disease of the elderly, but it is unclear whether aging itself is an independent contributor to the pathophysiology of these disorders. While the normal aged hematopoietic system and MDS share many features compared to young hematopoiesis, they also exhibit important differences. With the demonstration that mutations present in MDS can also be identified in healthy elderly individuals, it will be important to elucidate the differences and interactions between normal hematopoietic aging and MDS. Keywords Myelodysplastic syndromes, aging, hematopoietic stem cell, clonal hematopoiesis, mutation, bone marrow, microenvironment Disclosure: Carolien M Woolthuis and Christopher Y Park have nothing to disclose in relation to this article. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: January 15, 2016 Published Online: March 10, 2016 Citation: Oncology & Hematology Review, 2016;12(1):20–1 Correspondence: Christopher Y Park, Assistant Attending, Pathology and Clinical Laboratories Assistant Member, Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center 1275 York Ave, Box 20 New York, NY, 10065, US. E: parkc@mskcc.org The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic disorders, characterized by inefficient hematopoiesis, myeloid dysplasia, and an increased risk for developing acute myeloid leukemia (AML). 1,2 In the majority of patients, morbidity and mortality are the result of progressive cytopenias, but transformation to AML is observed in approximately one-third of patients. MDS is highly associated with age, illustrated by an increase in the incidence with advancing age and a median age at diagnosis of 65–70 years. While the pathophysiology of MDS is not fully understood, it is clear that it involves a multifactorial process that includes alterations in chromosomes, gene mutations, and changes in DNA methylation status in the hematopoietic cells. 1,2 Recent large-scale genome-sequencing studies have identified multiple recurrent gene mutations in MDS. These mutations affect genes involved in epigenetic regulation (e.g. DNMT3A, TET2, IDH1/2, EZH2, ASXL1) 3 and RNA splicing (e.g. SF3B1, SRSF2, U2AF1, ZRSR2) 4,5 among other pathways. In the majority of MDS cases more than one mutation can be detected. 6–8 Since MDS occurs primarily in elderly patients, it has been hypothesized that hematopoietic aging itself is an important factor in the pathophysiology of MDS. Indeed, hematopoietic stem cells (HSCs) in normal aged individuals and MDS patients exhibit similar differences when compared to normal young adults, including an increased frequency, myeloid skewing with diminished lymphoid potential, and decreased erythroid output. 9–11 However, whether age simply increases the probability of acquiring disease- 20 initiating mutations or whether cellular context itself contributes to disease pathogenesis is an unresolved question. Interest in this question has increased dramatically due to recent descriptions of clonal hematopoiesis in healthy elderly individuals. While the phenomenon of age-related clonal skewing in the bone marrow has been known for some time, the recent development of high-throughput genome sequencing has extended this observation by identifying presumed disease-initiating mutations in healthy individuals. 12–16 Indeed, the spectrum of mutations found in healthy elderly individuals with clonal hematopoiesis overlaps considerably with the mutations observed in MDS patients at diagnosis, including DNMT3A, TET2, and ASXL1 mutations. Blood-specific clonal mutations were identified in 5–6% of healthy people aged 70 years or older in one study 16 and clonal hematopoiesis was observed in 10% of individuals aged 65 and older in another cohort. 13 The detection of a clonal mutation is associated with an increased risk for developing a hematologic malignancy. However, the majority of individuals with a detectable clonal mutation did not develop a hematologic disease and actually died from non-hematologic causes. 13,14 This highlights the fact that the presence of a somatic clonal mutation is distinct from a diagnosis of MDS. In fact, it resembles more a condition like monoclonal gammopathy of undetermined significance (MGUS), which is associated with increased risk of developing clinically relevant B-cell lymphoproliferations. Based on these insights it was recently proposed that in patients without hematologic alterations, detection of a clonal mutation in a gene also recurrently mutated in hematologic malignancies could be classified as a separate entity, termed clonal hematopoiesis of indeterminate potential (CHIP). 17 This would recognize this condition while TOUCH ME D ICA L ME D IA