Key Points
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Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive haematopoietic malignancies that combine myeloid cell dysplasia and proliferation. Recognized entities are juvenile myelomonocytic leukaemia (JMML), chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia (aCML) and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
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JMML is a disease of young children that occurs as a result of de novo mutations or in the context of hereditary predisposition syndromes. JMML is considered a RASopathy, as somatic or germline mutations that activate the RAS pathway are common founder events whereas secondary mutations are less consistent.
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MDS/MPN are rare in middle age, but their incidence markedly increases in older individuals, and they can be regarded as one of the malignant conversions of age-related clonal haematopoiesis (ARCH). Mutations in epigenetic regulators may drive the early phases of these diseases, with mutations in signalling genes being acquired later during disease progression.
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Epigenetic dysregulation in MDS/MPN involves abnormal histone marking caused by inactivation of chromatin modifiers or abnormal DNA methylation resulting from mutations in DNA methyltransferases, splicing regulators or tet methylcytosine dioxygenase 2 (TET2).
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Hypersensitivity of myeloid progenitors to granulocyte–macrophage colony-stimulating factor (GM-CSF) is a hallmark of JMML and a common feature of CMML, especially when mutations are acquired in signalling genes. An inflammatory bone marrow microenvironment may favour neoplastic at the expense of normal haematopoiesis.
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Allogeneic stem cell transplantation is the only curative therapy and is commonly used for children with JMML, whereas many adult patients with MDS/MPN are poor transplant candidates owing to age and comorbidities.
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Hypomethylating agents normalize blood counts in a subset of patients, but rarely restore polyclonal haematopoiesis and have modest effect on survival. Current experimental therapies are focused on inhibiting activated signalling pathways.
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Novel therapeutic strategies may emerge from a better mechanistic understanding of the interactions between MDS/MPN cells and their stromal microenvironment. The functional capacity of residual normal haematopoietic cells will be crucial to any approach aimed at eliminating the MDS/MPN clone.
Abstract
Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress.
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Acknowledgements
The authors thank J. Ottley, Division of Haematology and Haematologic Malignancies, University of Utah, Salt Lake City, USA, for critically reading the manuscript. M.W.N.D. was supported by grants from the V Foundation for Cancer Research, National Institutes of Health/National Cancer Institute (R01CA178397; R21CA205936), and Leukemia and Lymphoma Society (GCNCR0314UTAH). J.W.T. was supported by the Leukemia and Lymphoma Society, the V Foundation for Cancer Research, the Gabrielle's Angel Foundation for Cancer Research and the National Cancer Institute (5R00CA151457-04; 1R01CA183947-01). E.S. was supported by grants from Ligue Nationale Contre le Cancer (Equipe labellisée), INCa (PRT2013 H78016; INCA_8073), and Investissements d'Avenir (Molecular Medicine in Oncology program).
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Clinical features of and diagnostic approach to MDS/MPN. (PDF 88 kb)
Glossary
- Ring sideroblasts
-
Erythroblasts with iron-loaded mitochondria visualized by Prussian blue staining (Perls' reaction) as a perinuclear ring of blue granules.
- Thrombocytosis
-
The presence of a high platelet count in the blood (also known as thrombocythaemia).
- Age-related clonal haematopoiesis
-
(ARCH). A state in which somatic mutations are found in cells of the blood or bone marrow of older individuals, but no other criteria for haematological neoplasia are met.
- X-chromosome inactivation
-
Early during somatic tissue development of female organisms, the maternal or the paternal copy of the X-chromosome is randomly inactivated, leading to the balanced expression of paternal and maternal X-chromosomal genes in a tissue; conversely, in a clonal population, the maternal or paternal X-chromosomes are nonrandomly inactivated.
- Thrombocytopenia
-
Decreased number of circulating platelets. Other cytopenias include anaemia (decreased numbers of red blood cells) and leukopenia (decreased numbers of leukocytes).
- Splenomegaly
-
Increased spleen size.
- Uniparental disomy
-
The presence of two identical copies of a given chromosome or part of a chromosome from one parent instead of one copy from the father and one from the mother.
- Mastocytosis
-
A condition that is characterized by infiltration of abnormal mast cells into the tissues of the body.
- Erythroblastic island
-
A group of erythroid precursors with a macrophage in the centre that provides iron for incorporation into haemoglobin in developing red blood cells.
- Vasculitis
-
One of a group of diseases characterized by inflammation of the blood vessel walls, in which patients exhibit symptoms such as fatigue, malaise, weakness and weight loss.
- Reduced intensity conditioning
-
Chemotherapy or radiotherapy, given before haematopoietic stem cell transplantation that does not completely destroy the bone marrow as is the case with standard myeloablative conditioning.
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Deininger, M., Tyner, J. & Solary, E. Turning the tide in myelodysplastic/myeloproliferative neoplasms. Nat Rev Cancer 17, 425–440 (2017). https://doi.org/10.1038/nrc.2017.40
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DOI: https://doi.org/10.1038/nrc.2017.40
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