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Myelodysplastic Syndromes (MDS)

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Pathophysiology

Myelodysplastic syndromes (MDS) are a group of clonal disorders characterized by mutational changes in the hematopoietic stem cells. This results in the disease-related features of ineffective hematopoiesis, dysplasia in 1 or more of the 3 blood cell lines, and cytopenia or cytopenias affecting 1 or more of these blood cell types.1

MDS develops due to a combination of environmental exposures and/or genetic factors that contribute to hematopoietic stem cell injury, increasing the risk of developing MDS.2

Risk Factors Promoting MDS Development

Exposure to environmental toxins may increase the likelihood of acquiring somatic mutations that foster clonal expansion, inflammatory processes, and dominance of the mutated hematopoietic stem cells.1 

Environmental exposures that increase MDS risk include1,2:

  • Benzene;
  • Radiation (from atomic bomb or nuclear reactor explosions);
  • Previous treatment with chemotherapy and/or radiation, especially long or intense bouts of treatment with alkylating chemotherapeutic agents, hydroxyurea, and topoisomerase inhibitors; and
  • Viral infections.

Read more about MDS risk factors

Chromosomal cytogenetic abnormalities occur frequently in MDS.1 Inherited germline mutations predispose these individuals to develop MDS at younger ages, sometimes during childhood.3,4

Read more about MDS genetics

Transformation of Bone Marrow

Bone marrow cells exhibit abnormal morphological changes and problems with maturation (dysmyelopoiesis) that cause ineffective blood cell production.5 Most cases of MDS demonstrate hypercellularity in the bone marrow, while around 10% to 15% demonstrate hypocellularity,5,6 defined as less than 30% cellularity in patients under 60 years of age or less than 20% cellularity in patients over 60 years of age.7 

Both hypercellularity and hypocellularity correlate with ineffective hematopoiesis. Hypercellularity in MDS is usually the result of the body’s attempt to compensate for ineffective hematopoiesis due to the low number of functional erythrocytes, neutrophils, and/or platelets.8 In hypocellular MDS, bone marrow failure results from 2 factors: the ineffective hematopoiesis of abnormal clones and the inhibition of normal progenitor cells, which further exacerbates the ineffective hematopoiesis.7

Ineffective Hematopoiesis and Cytopenias

The inability of stem cells to produce normal, functional, mature blood cells can result in anemia (most frequent), neutropenia, thrombocytopenia, or any combination of these conditions. Over time, patients with MDS who have significant, refractory, or chronic anemia gradually develop iron overload from repeated blood transfusions and/or increased intestinal iron absorption.1

Read more about MDS clinical features

Myelofibrosis in MDS

Myelofibrosis develops in approximately 10% to 20% of MDS cases.9 Myelofibrosis occurs when abnormal stem cells grow due to a lack of regulation caused by genetic mutations. This uncontrolled stem cell expansion results in bone marrow scarring and chronic inflammation.10

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Extramedullary Hematopoiesis

When the bone marrow can no longer produce sufficient quantities of functional blood cells, other organs, such as the liver and spleen, may begin to produce blood cells in a compensatory effort called extramedullary hematopoiesis. Extramedullary hematopoiesis may lead to the development of hepatomegaly or splenomegaly.1 

Blasts in Bone Marrow and Peripheral Blood

The World Health Organization (WHO) categorizes MDS subtypes according to several features, including specific genetic mutations, characteristic clinical or pathological features, and percentages of immature blast cells, or myeloblasts, located in samples of the bone marrow and peripheral blood.11 

Read more about MDS types

Accumulation of blasts in the peripheral blood and bone marrow less than 20% suggest MDS; accumulation of these same blasts at greater than 20% suggest acute myeloid leukemia (AML).11 Around one-third of MDS cases evolve into AML. Individuals diagnosed with lower-risk MDS demonstrate a 20% likelihood of transformation into AML, while individuals diagnosed with higher-risk MDS demonstrate a 40% likelihood of developing AML.12

Read more about MDS prognosis

Innate Immune Signaling and Inflammation in MDS

Overexpression of immune-related genes in hematopoietic stem and progenitor cells occurs in more than half of patients with MDS. Chronic innate immune signaling and associated inflammatory pathways contribute to the pathogenesis of MDS.13

Dysregulation of innate immune-related genes commonly occurs in affected stem cells in MDS. Chronic innate immune signaling (especially through activation of Toll-like receptors) leads to the recruitment of kinases, intracellular adaptors, and effector molecules, including IRAK1, IRAK4, and MyD88. TRAF6, a ubiquitin ligase that regulates innate immune receptor signals, may either be overexpressed or downregulated (a small subgroup of MDS patients). Overexpression of these molecules results in prolonged inflammation and impairment of normal hematopoiesis.13 

Elevated expression of cytokines, chemokines, and growth factors occurs in MDS, especially tumor necrosis factor-α, transforming growth factor-β, interferon ϒ, granulocyte-macrophage colony-stimulating factors, and interleukins 6, 8, and 1β. Prolonged inflammation alters the bone marrow microenvironment, promoting the development of MDS.13

References

  1. Emadi A, Law JY. Myelodysplastic syndrome (MDS). Merck Manual Professional Version. Updated September 2022. Accessed June 19, 2023.
  2. Besa EC. Myelodysplastic syndrome (MDS): pathophysiology. Medscape. Updated October 1, 2022. Accessed June 19, 2023.
  3. Myelodysplastic syndromes – MDS: risk factors. Cancer.Net. Accessed June 19, 2023.
  4. Feurstein S, Churpek JE, Walsh T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia. 2021;35(8):2439-2444. doi:10.1038/s41375-021-01137-0
  5. Besa EC. Myelodysplastic syndrome (MDS): practice essentials. Medscape. Updated October 1, 2022. Accessed June 19, 2023.
  6. Calabretto G, Attardi E, Teramo A, et al. Hypocellular myelodysplastic syndromes (h-MDS): from clinical description to immunological characterization in the Italian multi-center experience. Leukemia. 2022;36(7):1947-1950. doi:10.1038/s41375-022-01592-3
  7. Calado RT. Immunologic aspects of hypoplastic myelodysplastic syndrome. Semin Oncol. 2011;38(5):667-672. doi:10.1053/j.seminoncol.2011.04.006
  8. Morita K, Ali A, Coutinho D, Mushtaq MU, Raza A. Prognostic significance of bone marrow cellularity in myelodysplastic syndromes: a retrospective analysis. J Clin Oncol. 2016;34(15_suppl):e18550. doi:10.1200/JCO.2016.34.15_suppl.e18550
  9. Jain AG, Zhang L, Bennett JM, Komrokji R. Myelodysplastic syndromes with bone marrow fibrosis: an update. Ann Lab Med. 2022;42(3):299-305. doi:10.3343/alm.2022.42.3.299
  10. Myelofibrosis (MF). The Aplastic Anemia and MDS International Foundation. Accessed June 19, 2023.
  11. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
  12. Acute myeloid leukemia (AML). The Aplastic Anemia and MDS International Foundation. Accessed June 19, 2023.
  13. Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132(15):1553-1560. doi:10.1182/blood-2018-03-784116

Reviewed by Harshi Dhingra, MD, on 6/17/2023.

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