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  • Review Article
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Myelodysplastic syndromes: the complexity of stem-cell diseases

Key Points

  • Myelodysplastic syndromes (MDS) comprise the most common malignant blood disorder. MDS are increasing in frequency owing to an ageing population and increased awareness of these diseases.

  • MDS are characterized by ineffective haematopoiesis. The bone marrow cells seem to be abnormal, with dysplastic changes in the nucleus or cytoplasmic granules.

  • MDS can evolve from a refractory anaemia to acute myeloid leukaemia (AML), which is associated with a decrease in intramedullary apoptosis and a block in myeloid differentiation.

  • Previously known as 'preleukaemia' or 'smouldering leukaemia,' MDS can be distinguished from de novo AML through its suppression of normal haematopoiesis, the presence of apoptosis in the early stages of the disease, the presence of chromosome 5 or 7 abnormalities, the incidence of blast cells being less than 20%, normal cellular differentiation at onset, a poorer response to treatment with cytosine arabinoside and an older age at presentation.

  • One of the mysteries of MDS is how the stem cells that give rise to these syndromes differ from that of the AML stem cell. Although there are several genetically-defined mouse models of MDS, MDS stem cells are difficult to engraft in a xenotransplantation model.

  • MDS that arises in paediatric patients might be secondary to inherited bone marrow-failure syndromes (for example, Fanconi anaemia, severe congenital neutropaenia, Shwachman–Diamond syndrome or Diamond–Blackfan anaemia).

  • Most cases of adult MDS are sporadic, but some are due to exposure to genotoxic damage incurred during treatment with chemotherapy or ionizing radiation (therapy-related MDS; tMDS).

  • Allogeneic stem-cell transplant is the only known cure. Newer drug therapies have been directed toward reversing gene silencing by hypomethylating agents (5′-azacitidine or decitabine) or through alteration of the cytokine environment by lenalidomide.

Abstract

The prevalence of patients with myelodysplastic syndromes (MDS) is increasing owing to an ageing population and increased awareness of these diseases. MDS represent many different conditions, not just a single disease, that are grouped together by several clinical characteristics. A striking feature of MDS is genetic instability, and a large proportion of cases result in acute myeloid leukaemia (AML). We Review three emerging principles of MDS biology: stem-cell dysfunction and the overlap with AML, genetic instability and the deregulation of apoptosis, in the context of inherited bone marrow-failure syndromes, and treatment-related MDS and AML.

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Figure 1: MDS constitute a complex range of stem-cell diseases.
Figure 2: The hierarchical organization of haematopoiesis.
Figure 3: Role of apoptotic pathways in MDS.

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Acknowledgements

This work has been supported by grants from the US National Institutes of Health, the Canadian Institutes for Health Research, Leukemia Lymphoma Society, Ontario Cancer Research Network and the AA/MDS Foundation.

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Correspondence to Seth J. Corey.

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Hagop Kantarjian receives support from MGI and Pharmion.

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Seth Corey's laboratory webpage

Aplastic Anemia/MDS Foundation:

Leukemia and Lymphoma Society of America

Myelodsyplastic Syndromes Foundation

MD Anderson Leukemia Newsletter

Glossary

Dysplasia

Disordered growth: that is, an abnormally organized cell. The alterations include size, shape (pleomorphism), hypochromatic nuclei and also the architectural orientation of adult cells, generally representing a premalignant stage.

Blast

An immature blood cell found either in the bone marrow or bloodstream, which can be characterized as either lymphoid or myeloid.

Peripheral cytopaenia(s)

A deficiency of red blood cells (anaemia), granulocytes (neutropaenia) or platelets (thrombocytopaenia) detected in the bloodstream.

Mutator phenotype

A genetic predisposition to errors in DNA replication and repair.

Paroxysmal nocturnal haemoglobinuria

An acquired clonal disorder of haematopoiesis, caused by a somatic mutation in the X-linked PIGA gene, that arises in haematopoietic stem cells.

NOD/SCID;β2m−/− mice

T-cell and B-cell lymphocyte immunodeficient mice that have been rendered further immunocompromised through the genetic ablation of β2 microglobulin, a component of the major histocompatibility complex class I molecules. As a result, they also lack natural killer cell function and might serve as better recipients for human bone marrow stem-cell transplants.

NOD/SCID;γcnull mice

A mouse strain created from T-cell and B-cell lymphocyte immunodeficient mice that were backcrossed with mice with the genetic deletion of the γc chain of the interleukin 2 receptor family. These mice might have even better rates of engraftment of human bone marrow stem cells than NOD/SCID;2m−/− mice.

Pancytopaenia

Decreased levels of or the absence of primary haematopoietic cells in the bone marrow. There are decreased numbers of granulocytes, red blood cells and platelets in MDS.

Vav1 promoter

The Vav 1 promoter directs the synthesis of a 3.0 kb transcript that is specifically expressed in cells of haematopoietic origin, including those of erythroid, lymphoid, and myeloid lineages.

Pten+/−;Ship1−/− mice

These mice are heterozygous for two phosphotidylinositol 3 kinase pathway phosphoinositol phosphatases, PTEN and SHIP1.

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Corey, S., Minden, M., Barber, D. et al. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 7, 118–129 (2007). https://doi.org/10.1038/nrc2047

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