Myelodysplastic Syndromes

Abstract

The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with cytopenias leading to serious morbidity plus the additional risk of leukemic transformation. Therapeutic dilemmas exist in MDS because of the disease's multifactorial pathogenetic features, heterogeneous stages, and the patients' generally elderly ages. Underlying the cytopenias and evolutionary potential in MDS are innate stem cell lesions, cellular/cytokine-mediated stromal defects, and immunologic derangements. This article reviews the developing understanding of biologic and molecular lesions in MDS and recently available biospecific drugs that are potentially capable of abrogating these abnormalities.Dr. Peter Greenberg's discussion centers on decision-making approaches for these therapeutic options, considering the patient's clinical factors and risk-based prognostic category.One mechanism underlying the marrow failure present in a portion of MDS patients is immunologic attack on the hemopoietic stem cells. Considerable overlap exists between aplastic anemia, paroxysmal nocturnal hemoglobinuria, and subsets of MDS. Common or intersecting pathophysiologic mechanisms appear to underlie hemopoietic cell destruction and genetic instability, which are characteristic of these diseases. Treatment results and new therapeutic strategies using immune modulation, as well as the role of the immune system in possible mechanisms responsible for genetic instability in MDS, will be the subject of discussion by Dr. Neal Young.A common morphological change found within MDS marrow cells, most sensitively demonstrated by electron microscopy, is the presence of ringed sideroblasts. Such assessment shows that this abnormal mitochondrial iron accumulation is not confined to the refractory anemia with ring sideroblast (RARS) subtype of MDS and may also contribute to numerous underlying MDS pathophysiological processes. Generation of abnormal sideroblast formation appears to be due to malfunction of the mitochondrial respiratory chain, attributable to mutations of mitochondrial DNA, to which aged individuals are most vulnerable. Such dysfunction leads to accumulation of toxic ferric iron in the mitochondrial matrix.

Genomic landscape of CD34 + hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers

“…Evidence has been provided by molecular cytogenetics, gene expression profiles, and xenograft animal studies to suggest that hematopoietic stem/progenitor cells (HSPCs) involved in MDS pathogenesis, like in most AML settings, are enriched in CD34 + cell population. Among different subtypes of MDS according to World Health Organization (WHO) nomenclature, refractory anemia with excess blasts (RAEB) is of poor prognosis because a significant percentage of the patients progress to AML; patients with refractory cytopenia with multilineage dysplasia (RCMD) show a longer lifespan with heterogeneous risks, whereas other subtypes are usually considered as intermediate or low risk groups (2,3). Furthermore, the Revised International Prognostic Scoring System (IPSS-R) incorporates the common karyotype, the depth of cytopenias, and the percentage of blasts in bone marrow (BM) for improved prognostic prediction (4,5).…”

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

“…1 Usually, MDS patients are elderly and they already show anemia, leukopenia and/or thrombocytopenia at presentation. 2 Conventional diagnosis of MDS is based on a combination of morphology and cytogenetics, besides exclusion of other disorders as primary cause for cytopenia/dysplasia.…”

EVI1 induces myelodysplastic syndrome in mice

“…MDS is characterized by a stepwise progression of genetic abnormalities that can culminate in transformation to acute myeloid leukemia (17)(18)(19)(20)(21)(22)(23). However, as many as 40% of patients with MDS succumb to the consequences of cytopenia without leukemic transformation.…”