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  • Review Article
  • Published:

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

Key Points

  • Myelodysplastic syndrome (MDS) is one of the most common haematological malignancies and is associated with increased age and exposure to previous chemotherapy and radiation. It is characterized by cytopenias, morphological dysplasia and a propensity to transform to acute myeloid leukaemia (AML).

  • Clonal haematopoiesis of indeterminate potential (CHIP) is a condition in which a substantial percentage of haematopoietic cells bear a somatic mutation in a gene that is recurrently mutated in haematological malignancies, including MDS. CHIP is strongly associated with age and an increased risk of haematological malignancy.

  • More than 50 recurrently mutated genes have been identified in MDS, many of which occur in genes encoding RNA splicing factors, epigenetic regulators, haematopoietic transcription factors and kinase signalling pathways.

  • Individual mutations in MDS are associated with specific morphological findings, have independent prognostic significance and can predict response to therapy in some cases.

  • AML that arises out of a pre-existing MDS can be distinguished from de novo AML by the presence of specific mutations, such as those in splicing factors and certain epigenetic regulators.

  • Some mutations are associated with increased sensitivity or resistance to standard therapeutic interventions, providing new targets for the development of novel therapeutic agents.

  • Currently, allogeneic haematopoietic stem cell transplantation is the only known curative treatment for MDS.

Abstract

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

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Figure 1: Recurrent mutations in CHIP and MDS.
Figure 2: Clonal expansion in MDS.
Figure 3: Splicing factor mutations in myeloid neoplasms.
Figure 4: Multiple steps in gene expression are recurrently disrupted in MDS.
Figure 5: Mechanism of lenalidomide efficacy in 5q syndrome.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (NIH) (R01 HL082945 and R24 DK099808), the Department of Defense, the Edward P. Evans Foundation, the Leukemia and Lymphoma Society and the STARR Cancer Consortium to B.L.E.

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Correspondence to Benjamin L. Ebert.

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B.L.E. receives research funding from Celgene, consulting fees from H3 Biomedicine, and consulting fees and patent royalties from Genoptix. The other authors declare no competing interests.

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Glossary

Cytopenias

Decreased blood counts of any kind (white cells, red cells or platelets).

Blasts

Immature, hypofunctional leukaemic cells found in the peripheral blood or bone marrow.

Secondary AML

(sAML). Acute myeloid leukaemia (AML) that arises out of a pre-existing myeloid neoplasm such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasms. Distinguished from MDS by the presence of 20% or more blasts in the bone marrow or peripheral blood.

Lineage

A collection of cell surface markers that defines mature blood cells, including B cells, T cells, monocytes, granulocytes and red blood cells.

5q syndrome

Myelodysplastic syndrome associated with isolated deletion of chromosome 5q and characterized by a macrocytic anaemia, normal or elevated platelet count, a low marrow blast count and a relatively indolent course.

Paroxysmal nocturnal haemoglobinuria

(PNH). Caused by mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene leading to the loss of glycosylphosphatidylinositol (GPI), a chemical linker that functions to anchor several proteins to blood cell membranes including those that block complement-mediated haemolysis.

Aplastic anaemia

(AA). Pancytopenia in the setting of aplastic bone marrow caused by immune-mediated destruction of haematopoietic progenitors. It is often difficult to distinguish morphologically from hypoplastic myelodysplastic syndrome.

Hypoplastic MDS

Myelodysplastic syndrome (MDS) with low bone marrow cellularity. Hypoplastic MDS can be difficult to distinguish from aplastic anaemia owing to the small number of cells available to evaluate for morphological dysplasia.

Mean corpuscular volume

(MCV). A measure of the average volume of red blood cells. Increased size is associated with abnormal or delayed red blood cell differentiation.

Clonal haematopoiesis of indeterminate potential

(CHIP). The presence of a somatic mutation associated with haematological malignancy at a variant allele fraction of at least 2% and the absence of morphological evidence of malignancy or diagnostic criteria for paroxysmal nocturnal haemoglobinuria, monoclonal gammopathy of undetermined significance or monoclonal B-lymphocytosis.

Hazard ratio

A statistical measure that corresponds to the probability of a particular outcome attributable to a given variable compared with normal controls.

Annual risk

The probability of acquiring a condition over the course of 1 year.

Idiopathic cytopenias of undetermined significance

(ICUS). Cytopenias that remain unexplained after thorough evaluation and do not meet World Health Organization criteria for a haematological neoplasm.

de novo AML

Acute myeloid leukaemia (AML) that arises without a pre-existing myeloid neoplasm or a history of cytotoxic therapy. More common in younger patients and associated with an overall better prognosis.

Induction therapy

High-dose intensive chemotherapy directed at inducing remission in acute leukaemias.

Polycomb repressive complex

(PRC). Multiprotein complex involved in epigenetic repression of gene transcription.

Cohesin complex

A multisubunit protein complex that forms a ring structure capable of encircling two chromosomal strands of DNA and is required for sister chromatid cohesion during mitosis.

Core binding factor

A core haematopoietic transcription factor complex, mutations of which are associated with acute myeloid leukaemia in younger patients and a relatively good prognosis.

Red cell distribution width

A measure of the distribution of red blood cell sizes; indicates the degree of variation within a sample.

Polycythemia vera

(PV). Myeloproliferative neoplasm characterized by an elevated red blood cell count, and almost exclusively associated with activating mutations in Janus kinase 2 (JAK2).

Essential thrombocythemia

(ET). Myeloproliferative neoplasm characterized by elevated platelet count, associated with mutations in Janus kinase 2 (JAK2), calreticulin (CALR) or MPL (gene that encodes the thrombopoietin receptor).

Ring sideroblasts

Early red cell precursors containing aberrant mitochondrial iron staining; associated with mutations in splicing factors, most commonly splicing factor 3b subunit 1 (SF3B1).

Conditioning regimens

High-dose preparative chemotherapy regimens given before stem cell transplantation. Can be either myeloablative (doses sufficient to completely ablate the bone marrow) or non-myeloablative.

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Sperling, A., Gibson, C. & Ebert, B. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer 17, 5–19 (2017). https://doi.org/10.1038/nrc.2016.112

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