Myelodysplastic syndromes: molecular pathogenesis and genomic changes (original) (raw)

The Molecular Anatomy of Myelodysplastic Syndromes: An Update

Journal of Advances in Medicine and Medical Research, 2018

Aims: Myelodysplastic syndromes (MDS) are a group of clonal haematopoietic disorders arising from blood stem cells. Their main characteristics are a wide range of cytopenias and ineffective haematopoiesis. The purpose of this review was to summarise the current knowledge on the molecular biology of MDS the impact of gene mutations on the outcome of the disease. Materials and Methods: A thorough search of PubMed was conducted and a review of the current literature. Results: The introduction of novel techniques in molecular biology (real-time PCR, next generation sequencing) has led to the identification of a series of mutations associated with prognosis of MDS patients and response to therapy and the development of novel prognostic models classifying MDS patients into risk groups. Those mutations include chromosomal aberrations and point mutations involving genes associated with mRNA splicing, methylation, signal transduction, regulation of transcription and cell cycle and other cellular pathways. Conclusion: Further studies will be needed in order to define the precise role of those mutations in prognosis and therapy of MDS.

Stem Cells in the Myelodysplastic Syndromes

Frontiers in Aging, 2021

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression fro...

Myelodysplastic syndromes: an update on molecular pathology

Clinical and Translational Oncology, 2010

The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterised by impaired peripheral blood cell production due to bone marrow dysplasia affecting one or more of the major myeloid cell lines. MDS are one of Þ ve major categories of myeloid neoplasms according to the World Health Organization (WHO) classiÞ cation system for haematological cancers. Given their cytological and cytogenetic heterogeneity, these diseases probably constitute a group of molecularly distinct entities with variable degrees of ineffective haematopoiesis and susceptibility to leukaemic transformation. Recent studies provide some insights into the physiopathology of MDS. In the early stages, one mechanism contributing to hypercellular marrow and peripheral blood cytopenia is a signiÞ cant increase in programmed cell death (apoptosis) in haematopoietic cells. Furthermore, altered responses in relation to cytokines, the immune system and bone marrow stroma also contribute to the disease phenotype. Deletions of chromosome 5q31-q32 are the most common recurring cytogenetic abnormalities detected in MDS. The 5q-syndrome is a new entity recognised in the WHO classiÞ cation since 2001 and is associated with a good prognosis. Haplo-insufÞ ciency of multiple genes mapping to the common deleted region at 5q31-32 may contribute to the pathogenesis of 5q-syndrome and other MDS with 5q-deletion. Many studies have demonstrated that altered DNA methylation and histone acetylation can alter gene transcription. Abnormal methylation of transcription promoter sites is universal in patients with MDS, and the number of involved loci is increased in high-risk disease and secondary leukaemias. A better understanding of the pathogenesis of MDS can contribute to the development of new treatments such as hypomethylating drugs, immunomodulatory agents such as lenalidomide, and immunosuppressive drugs aimed at reversing the speciÞ c alteration that results in improvement in patients with MDS.

Cytogenetic abnormalities in myelodysplastic syndrome: an overview

Hematology, 2011

The myelodysplastic syndromes (MDS) are clonal disorders of haematopoietic stem cells characterized by ineffective haematopoiesis leading to blood cytopenias and by high incidence of progression to acute myeloid leukaemia (AML). These disorders generally arise de novo, but may also occur years after exposure to mutagenic chemotherapy. Clonal cytogenetic abnormalities are detected in about 30-50% de novo cases, whereas more than 80% of therapy-related forms harbour such markers. Although in the Western countries, MDS cases are mainly reported in the elderly population and rarely in the paediatric age group; this disease is increasingly seen in young adults in India. Cytogenetic study plays an important role in the diagnosis and is useful for prediction of individual prognosis using the international prognostic scoring system. Specific chromosomal abnormalities, such as 25/5q-, 27/7q-, and complex abnormalities, play an important role in the development of new therapeutic options and clinical management of MDS. In this review, we summarize the cytogenetic abnormalities in MDS from various parts of the world.

Mechanisms underlying the heterogeneity of myelodysplastic syndromes

Experimental Hematology

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) disorders in which recurrent chromosome abnormalities and gene mutations define a clonal hematopoiesis. The MDSinitiating cell is a rare HSC which transmits the genetic abnormalities to its myeloid and lymphoid progeny. The heterogeneity of MDS phenotypes could be linked to the diversity of genetic events involving epigenetic regulators, chromatin modifiers, splicing factors, transcription factors and signaling adaptors, the various combinations and order of mutations in cooperating genes, and the variegation of clonal hematopoietic hierarchy. Usually, epigenetic and splicing gene mutations occur first. A combination of one epigenetic event with a splicing gene alteration is frequent. The HSC compartment is invaded by a dominant and few minor clones organized linearly or with a branched architecture. The dominant clone containing the first initiating mutations produces myeloid and lymphoid lineages in transplanted immune-deficient mice. The mutations confer a selective advantage to myeloid progenitors at the expense of lymphoid progenitors. In the context of differentiation, one mutation may favor the amplification of granulomonocytic progenitor, which drives the transformation into acute myeloid leukemia. Understanding the hierarchy of mutations provides insights on the mechanism of transformation. Investigation of mutation pattern and distribution along the hematopoietic tree may influence the therapeutic decision for targeted therapy.

Myelodysplastic syndromes: recent advances

Haematologica, 2001

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