Molecular basis of myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more cell lines, ineffective hematopoiesis and variable risk of progression to acute myeloid leukemia. In the past few years, important steps have been taken in characterizing the molecular basis of MDS. More recently, somatic mutations in genes encoding core components of the RNA splicing machinery have been detected in high proportions of MDS patients, and are shown to be founding mutations in many instances. These mutations have different clinical significance, and their incorporation into current stratification systems might improve risk assessment in MDS.

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more cell lines, ineffective hematopoiesis and variable risk of progression to acute myeloid leukemia (AML).¹ The World Health Organization (WHO) classification criteria² for MDS diagnosis require evaluation of peripheral blood and bone marrow morphology, combined with cytogenetic analyses, and define the following categories:³ refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts (RAEB) type 1 (RAEB-1) and 2 (RAEB-2), and MDS with isolated (del 5q)).

These conditions are heterogeneous in terms of life expectancy,⁴ and risk-based stratification systems have been developed to improve their prognostication, including the International Prognostic Scoring System (IPSS)⁵ and the WHO classification-based Prognostic Scoring System (WPSS).⁶ Both IPSS and WPSS are currently being revised by the International Working Group for Prognosis in MDS to improve their ability to predict the outcome of MDS patients. As comorbidities have a significant impact on clinical outcome, accounting for both disease status and comorbid conditions considerably improves risk stratification in MDS.⁷

In the past few years, important steps have been taken in characterizing the molecular basis of MDS, and in developing novel molecular tools for diagnosis and prognostic evaluation of these myeloid neoplasms. Acquired somatic mutations of TET2 have been detected in approximately 25% of MDS patients.^{8, 9} TET2 mutations represent a useful marker of clonal proliferation, although they do not carry prognostic relevance.¹⁰ Additional mutant genes, including TP53, EZH2, ETV6, RUNX1 and ASXL1, have been identified in smaller proportions of patients, but mutations in these latter genes have been shown to be independently associated with decreased overall survival in MDS.¹¹

More recently, somatic mutations in genes encoding core components of the RNA splicing machinery have been detected in high proportions of MDS patients.^{12, 13, 14, 15, 16, 17} The close association between mutations in one of these genes, SF3B1, and disease phenotype with ring sideroblasts is consistent with a causal relationship.¹⁸ In addition, SF3B1 mutations are independent predictors of favorable clinical outcome, especially of low risk of leukemic evolution.¹⁸ On the contrary, mutations of SRSF2 or U2AF1, other genes encoding spliceosome components, are associated with unfavorable clinical outcome and a high risk of progression to (AML).^{14, 15, 16, 17} Incorporation of these mutant genes into current stratification systems might improve risk assessment in MDS.

The recent advances in our understanding of the molecular basis of MDS have also allowed to decipher, at least in part, the pathophysiology of myelodysplastic/myeloproliferative neoplasms,¹⁹ such as refractory anemia with ring sideroblasts associated with marked thrombocytosis and chronic myelomonocytic leukemia.^{20, 21, 22}

The author declares no conflict of interest.