Stem Cell Dysfunction

Stem cell dysfunction in myelodysplastic syndromes (MDS) leads to abnormal cell development.1 To understand stem cell dysfunction in MDS, it’s important to understand how stem cells function in healthy individuals.

Stem cells in healthy people

  • In healthy people, hematopoietic stem cells (HSCs) in bone marrow differentiate and mature (develop) into 3 types of blood cells that are released into the peripheral blood2,3:
    • Erythrocytes, or red blood cells (RBCs), which carry oxygen around the body3
    • White blood cells (WBCs), such as neutrophils, which fight infections3
    • Platelets, which help form blood clots3

Learn more about normal blood cell development.

Stem cells in people with MDS

  • In contrast, HSCs in patients with MDS may have mutations that contribute to disease pathogenesis4
  • These abnormal cells may not be able to mature completely, accumulate in the bone marrow, or have a shortened life span, thereby leading to underproduction of mature blood cells in the peripheral blood4
  • Blood cells that do enter the peripheral blood may not function properly due to morphologic abnormalities (eg, abnormal shape and size), also known as dysplasia4
  • Dysplastic cell formation and the lack of normal blood cell production results in peripheral-blood cytopenias1:
    • Anemia (low RBC count) can lead to fatigue
    • Leukopenia/neutropenia (low WBC count) can lead to infection
    • Thrombocytopenia (low platelet count) can lead to bleeding and bruising

From stem cell to abnormal blood cell development in MDS2,4


Factors leading to stem cell dysfunction in MDS

Many factors have been identified that can cause stem cell dysfunction and therefore lead to MDS. A number of these factors are described below; however, there are still some unknown factors that can lead to MDS in some cases.3,5

Environmental Exposure to mutagens may increase the risk of MDS.5,6

  • Examples include: benzene, fertilizers, pesticides, radiation

Patient-related Certain factors related to patient characteristics and history increase the risk for developing MDS.5,7 Advanced age is the greatest risk factor.5

  • Other examples include: gender, alcohol, tobacco, previous chemotherapy treatments5,6
Somatic Mutations Mutations in key regulatory molecules involved in the pathogenesis of MDS, including transcription factor alterations, signal-transduction factor alterations, and gene-splicing mutations, have been described.8,9
DNA Damage MDS are proposed to be associated with an inability to adequately respond to DNA damage, partly due to deficient DNA-repair mechanisms.10
Epigenetics Accrual of epigenetic aberrations has been implicated in stem cell dysfunction and MDS, with DNA methylation and histone-modification changes resulting in aberrant differentiation.8
Genetic Disorders Certain inherited disorders, such as Down syndrome and familial platelet disorder, may result in an accumulation of stem cell changes that can lead to MDS.11
Stem Cell Senescence Senescence (a state of permanent growth arrest) of mesenchymal stromal cells (cells that can differentiate into different types of cells) in the bone marrow has been reported in MDS.12

Initial genetic events responsible for progression to MDS can promote the acquisition of secondary genetic changes, which typically results in chromosomal changes associated with progression to AML.13

References: 1. Steensma DP. Myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2015;90(7):969-983. 2. Dean L. Blood Groups and Red Cell Antigens. Bethesda, MD: National Center for Biotechnology Information (US); 2005. Available at: http://www.ncbi.nlm.nih.gov/books/NBK2263. Accessed October 12, 2018. 3. American Cancer Society. What causes myelodysplastic syndromes? https://www.cancer.org/cancer/myelodysplastic-syndrome/causes-risks-prevention/what-causes.html. Accessed October 17, 2018. 4. Yoshida Y. Physician education: myelodysplastic syndrome. Oncologist. 1996;1(4):284-287. 5. Sekeres MA. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw. 2011;9(1):57-63. 6. Pagano L, Caira M, Fianchi L, et al. Environmental risk factors for MDS/AML. Haematol Rep. 2006;2:42-45. 7. Perdersen-Bjergaard J, Christiansen DH, Andersen MK, et al. Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities. Leukemia. 2002;16(11):2177-2184. 8. Issa JP. The myelodysplastic syndrome as a prototypical epigenetic disease. Blood. 2013;121(19):3811-3817. 9. Shih AH, Levine RL. Molecular biology of myelodysplastic syndromes. Semin Oncol. 2011;38:613-620. 10. Zhou T, Chen P, Gu J, et al. Potential relationship between inadequate response to DNA damage and development of myelodysplastic syndrome. Int J Mol Sci. 2015;16(1):966-989. 11. Mateos MK, Barbaric D, Byatt SA, et al. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl Pediatr. 2015;4(2):76-92. 12. Fei C, Zhao Y, Guo J, et al. Senescence of bone marrow mesenchymal stromal cells is accompanied by activation of p53/p21 pathway in myelodysplastic syndromes. Eur J Haematol. 2014;93(6):476-486. 13. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal hematopoiesis to secondary leukemia. Nat Rev Cancer. 2017;17(1):5-19.