Have we reached a molecular era in myelodysplastic syndromes?

Abstract

Myelodysplastic syndromes (MDS) are characterized by heterogeneous biological and clinical characteristics, leading to variable outcomes. The availability of sophisticated platforms of genome sequencing allowed the discovery of recurrently mutated genes, which have led to a new era in MDS. This is reflected by the 2016 update of the World Health Organization classification, in which the criteria to define MDS with ringed sideroblasts include the presence of SF3B1 mutations. Further, the detection of somatic mutations in myeloid genes at high variant allele frequency guides the diagnostic algorithm in cases with cytopenias, unclear dysplastic changes, and normal karyotypes, supporting MDS over alternative diagnoses. SF3B1 mutations have been shown to play a positive prognostic role, while mutations in ASXL1, EZH2, RUNX1, and TP53 have been associated with a dismal prognosis. This is particularly relevant in lower- and intermediate-risk disease, in which a higher number of mutations and/or the presence of "unfavorable" somatic mutations may support the use of disease-modifying treatments. In the near future, the incorporation of mutation profiles in currently used prognostication systems, also taking into consideration the classical patient clinical variables (including age and comorbidities), will support a more precise disease stratification, eg, the assignment to targeted treatment approaches or to allogeneic stem cell transplantation in younger patients.

Graphical abstract

Figure 1.

Perls' Prussian blue stain of the patient's BM smear showing RS. Classical type 3 RS are shown (according to Mufti et al), with multiple siderotic granules in a perinuclear position surrounding the nucleus (lower-right cell) or encompassing at least one-third of the nuclear circumference (middle cell).

Figure 2.

Model of disease evolution in MDS. Upper panel: risk factors commonly associated with the development of myeloid disorders (germline variants, smoking, aging, and cancer treatment exposure such as chemo/radiotherapy). Middle panel: a hypothetical model of clonal evolution in which the founding event (or germline predisposition lesion) leads to subsequent acquisition/loss of new somatic mutations in a linear/branching fashion. Lower panel: the typical acquisition of methylation during MDS progression, which leads to the silencing of genes such as tumor suppressor and the disruption of many cell pathways (DNA repair, apoptosis, cell cycle, cell adherence).

Figure 3.

Time course of the identification of genes involved in myeloid neoplasms with germline predisposition. Time line depicting the discovery of the most important genes involved in the development of myeloid disorders with germline predisposition. Different colors represent the associated peculiar features (eg, platelet disorders or organ dysfunction). For gene groups (eg, Fanconi anemia), the year of discovery of the first gene associated with the disease is indicated.

Figure 4.

Exemplificative list of genes recurrently mutated in MDS, with impact on clinical features and on treatment options. Shown are exemplary gene mutations, their prognostic impact, the associated recurrent clinical features, and possible therapeutic interventions.

Figure 5.

Clinicobiological characterization of MDS and tailored treatment. MDS patients represent a heterogeneous multitude characterized by different clinical, karyotypic, morphologic, and molecular features. In particular, the lower panel demonstrates how the incorporation of molecular information into currently available prognostication schemes will enable in the near future better prognostication and tailored treatments.