Blood Res.  2014 Dec;49(4):216-227. 10.5045/br.2014.49.4.216.

Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease

Affiliations
  • 1Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
  • 2Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, OH, USA.
  • 3Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA. rogersj5@ccf.org

Abstract

Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5-azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS.

Keyword

MDS; Molecular mutation; Pathogenesis

MeSH Terms

Asian Continental Ancestry Group
Cell Transplantation
Europe
Hematopoiesis
Hematopoietic Stem Cells
Humans
Incidence
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes*
Myeloid Cells
Polymorphism, Single Nucleotide
Prognosis
Transplants
United States

Figure

  • Fig. 1 Diagram of the histopathologic, cytogenetic, and molecular genetic tools for comprehensive evaluation of diagnosis, classification and prognosis in myelodysplastic syndrome. (A) Dyserythropoiesis (a) and dysmegakaryopoiesis and dysgranulopoiesis (b) in bone marrow aspirate smears (Wright Giemsa stain ×1,000). (B) Conventional cytogenetics showing a 45,XX,del(5)(q22q35),-7,der(17)t(7;17)(p12;p11.2),-8,der(11) t(8;11)(q11.2;p11.2),+mar karyotype. (C) Fluorescence in situ hybridization detecting the deletion of the long arm of chromosome 20 with one orange signal using LSI D20S108 probe (target locus on 20q12) and two green signals using CEP 8 probe (target locus on 8p11.1-q11.1) (Abbott Molecular, Abbott Park, IL, USA). (D) Representative single nucleotide polymorphism arrays (SNP-A) analysis of loss of heterozygosity (LOH), uniparental disomy (UPD) and gain lesions. The first and top track shows LOH (red brackets), the second track shows copy number for each SNP (blue brackets) and the third track shows the genotype calls (purple brackets). Allele calls are: AA, AB, BB are indicated. Vertical lines indicate each region of the genome. (E) Chromatogram of Sanger sequencing showing the forward sequencing of SF3B1 exon 15 illustrating the most frequent missense mutation (AAA>GAA;K700E; c.2098 G>A).


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