Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a heterogeneous group of rare, hematological neoplasms that are clonal disorders of hematopoietic stem cells in the bone marrow. Cytogenetic changes to the DNA of these multipotent stem cells result in the production of immature, abnormally shaped, and/or dysfunctional blood cells that affect 1 or more of the 3 major blood cell lineages: erythroid, megakaryocytic, and granulocytic. This, in turn, leads to decreased numbers of functional blood cells, resulting in a variety of signs of symptoms.1 

These cytogenetic stem cell abnormalities have been associated with changes in clonal architecture that lead to the promotion of an inflammatory microenvironment in the bone marrow and subsequent clonal expansion, resulting in MDS.1 

Integral Role of Inflammatory Signaling

Proinflammatory cytokines contribute to the ineffective hematopoiesis that occurs in MDS. In particular, tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) contribute to bone marrow progenitor cell death. The innate immune system plays a major role in inflammatory signaling in MDS.2

Activation of the innate immune system initiates a signaling cascade that drives antimicrobial host defense and the response of the adaptive immune system. In particular, IRAK1, a serine/threonine kinase, and TRAF6, an E3 ubiquitin ligase, play fundamental roles in MDS pathogenesis. Overexpression of these 2 proteins activates the innate immune system signaling cascade in MDS. Overexpression of TRAF6 leads to megakaryocytic dysplasia, neutropenia, and thrombocytosis.2

Other components of the innate and adaptive immune systems demonstrate dysregulation in patients with MDS, including macrophages, natural killer cells, and certain T lymphocytes. The exact relationship between inflammatory signaling and these immune cell interactions is not well understood.2

NLRP3 inflammasome activation has been shown to correlate with characteristic MDS features, such as macrocytosis, ineffective hematopoiesis, and β-catenin-instructed proliferation.2 This activation also directs pyroptosis in lower-risk MDS cases driven by cell-intrinsic somatic gene mutations and cell-extrinsic alarmins, such as S100A8/A9.2 

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Possible Causes for Cytogenetic Changes

Studies indicate that cytogenetic changes to stem cell DNA may occur due to certain risk factors, such as environmental or occupational exposures, previous treatment with chemotherapy (especially alkylating agents) and/or radiation leading to therapy-related MDS (t-MDS), and germline or somatic drivers causing recurrent cytogenetic abnormalities and gene mutations.3 

Therapy-related MDS is more commonly associated with monosomies in chromosomes 5 and 7 as well as complex karyotyping. It also more commonly transforms into acute myeloid leukemia (AML).3

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Genetic Mutations

Several genetic mutations observed in patients with MDS are inherited (germline predispositions), but most are somatic mutations, which are acquired during the course of a person’s lifetime. This may explain why MDS occurs most commonly in older people, with a median age of onset around 70 years of age.4,5

Germline Predispositions/Inherited Genetic Mutations

Myelodysplastic syndromes can affect individuals under the age of 40 years and, rarely, children. Children impacted by MDS exhibit a higher incidence of familial or hereditary syndromes and a different mutational landscape than adults with MDS.5 

Around 15% of MDS cases involve hypoplastic MDS subtypes, which are more commonly seen due to germline mutations.4 Germline predispositions are inherited genetic mutations that cause certain conditions that increase the likelihood of developing MDS.4,6,7

Somatic Genetic Mutations

Somatic mutations have been identified in more than 50 different genes and in 80% to 90% of individuals with various subtypes of MDS.1,3,4 Sources differ regarding the median number of somatic mutations, ranging from 3 to 9.1,4 The average number of somatic mutations depends on the MDS subtype, with fewer mutations observed in low-risk MDS subtypes (median: 6) and additional mutations observed in overlap syndromes (median: 12 in chronic myelomonocytic leukemia).4

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Contribution of Inherited and Somatic Genetic Changes

Genes affected by somatic or germline mutations can interfere with the body’s control over cellular division and proliferation (via oncogenes) and cellular apoptosis (via tumor suppressor genes).6 In particular, pyroptosis, rather than apoptosis, drives cell death in MDS.2 Neoplasms such as MDS can result from genetic mutations that activate oncogenes or inhibit tumor suppressor genes.6 

Somatic mutations in MDS affect specific cellular pathways, such as RNA splicing, DNA transcription, signal transduction, and epigenetic regulation.1 Scientists have identified over 100 mutated MDS genes that encode spliceosome components, transcription factors, epigenetic pattern modulators, and chromatin remodeling factors, as well as other proteins.3

Clonal Hematopoietic Expansion and Disease Progression

Certain somatic mutations are believed to initiate clonal hematopoietic expansion, including DNMT3A, TET2, ASXL1, SF3B1, JAK2, and TP53. Other, most likely subsequent, genetic mutations may support disease progression in conditions like MDS, myeloproliferative neoplasms (MPN), and AML, including NRAS, RUNX1, NPM1, and FLT3.8

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  1. Shallis RM, Ahmad R, Zeidan AM. The genetic and molecular pathogenesis of myelodysplastic syndromes. Eur J Haematol. 2018;101(3):260-271. doi:10.1111/ejh.13092
  2. Sallman DA, List A. The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes. Blood. 2019;133(10):1039-1048. doi:10.1182/blood-2018-10-844654
  3. Dotson JL, Lebowicz Y. Myelodysplastic syndrome. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated July 18, 2022. Accessed June 15, 2023. 
  4. Saygin C, Godley LA. Genetics of myelodysplastic syndromes. Cancers (Basel). 2021;13(14):3380. doi:10.3390/cancers13143380
  5. Sallman DA, Padron E. Myelodysplasia in younger adults: outlier or unique molecular entity? Haematologica. 2017;102(6):967-968. doi:10.3324/haematol.2017.165993
  6. What causes myelodysplastic syndromes? American Cancer Society. Updated January 22, 2018. Accessed June 15, 2023.
  7. Myelodysplastic syndromes – MDS: risk factors. Cancer.Net. Accessed June 15, 2023.
  8. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472-1478. doi:10.1038/nm.3733

Reviewed by Harshi Dhingra, MD, on 6/15/2023.