Unraveling the molecular pathophysiology of myelodysplastic syndromes

Abstract

Somatically acquired genetic abnormalities lead to the salient features that define myelodysplastic syndromes (MDS): clonal hematopoiesis, aberrant differentiation, peripheral cytopenias, and risk of progression to acute myeloid leukemia. Although specific karyotypic abnormalities have been linked to MDS for decades, more recent findings have demonstrated the importance of mutations within individual genes, focal alterations that are not apparent by standard cytogenetics, and aberrant epigenetic regulation of gene expression. The spectrum of genetic abnormalities in MDS implicates a wide range of molecular mechanisms in the pathogenesis of these disorders, including activation of tyrosine kinase signaling, genomic instability, impaired differentiation, altered ribosome function, and changes in the bone marrow microenvironment. Specific alterations present in individual patients with MDS may explain much of the heterogeneity in clinical phenotype associated with this disease and can predict prognosis and response to therapy. Elucidation of the full complement of genetic causes of MDS promises profound insight into the biology of the disease, improved classification and prognostic scoring schemes, and the potential for novel targeted therapies with molecular predictors of response.

Fig 1.

Targets of point mutations and deletions in myelodysplastic syndromes. Mutations in multiple pathways have been implicated in the pathogenesis of myelodysplastic syndromes. Features shown in red are targets of activating mutations, whereas mutations or deletions of features in blue result in a loss of function. Mutations that impair function may also cause a gain of function as is believed to be the case for a subset of mutations in CBL, ASXL1, NPM1c, IDH1/ IDH2, TP53, and RUNX1.

Fig 2.

Various pathways to transformation. The defining feature of myelodysplastic syndromes is clonal and inefficient hematopoiesis that causes peripheral cytopenias. A heterogeneous set of genetic and epigenetic abnormalities drive the cellular events that give rise to clinical phenotypes. Individual lesions may be responsible for one transformative step alone (eg, enhanced self-renewal or altered apoptosis) and therefore be clinically silent in isolation, or they could result in several abnormalities (eg, acquired self-renewal and impaired differentiation). Cooperation between two or more lesions is likely needed for the full expression of disease.