The genetic basis of myelodysplasia and its clinical relevance

Abstract

Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed.

Figure 1

Representative examples of morphologic abnormalities of myelodysplasia. May Grünwald Giemsa staining in all cases with the only exception of ring sideroblasts (Perls staining). Magnification from 200× to 1000×, courtesy of Erica Travaglino.

Figure 2

Schematic representation of our current understanding of the pathophysiology of myelodysplasia. In this example, the founding driver mutation is assumed to occur in a hematopoietic cell located in the bone marrow of the right ilium, and the sternum is shown as an anatomically separated bone marrow district to illustrate the concept of mutated stem cell migration through peripheral blood. Bone marrow microphotographs: magnification from 600×, courtesy of Erica Travaglino.

Figure 3

Schematic representation of our current knowledge of genotype/phenotype relationships in MDS, MDS/MPN, and a related MPN like CNL. The SF3B1 mutation is strictly associated with RARS, whereas the combination of the SF3B1 mutation with subclonal driver mutations in JAK2 or MPL is associated with RARS-T. Thus far, no conclusive genotype/phenotype relationship has been defined within refractory cytopenia with unilineage dysplasia. Various combinations of founding and subclonal driver mutations can be found in RCMD and RAEB. CMML has a relatively well-defined molecular basis, involving primarily somatic mutations of TET2 and SRSF2: comutation of these genes is almost invariably associated with CMML, whereas the ASXL1 mutation involves poor outcome. Within MDS/MPN, aCML is characterized by various founding mutations plus a subclonal mutation of SETBP1. Activating mutations of CSF3R are strictly associated with CNL.

Figure 4

Current approach to diagnosis and prognostication of MDS and MDS/MPN and a hypothetical future approach based on massive parallel sequencing.

Figure 5

Kaplan-Meier analysis of overall survival and leukemia-free survival of 1110 patients diagnosed with MDS at the Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, between 1990 and 2012. MDS patients are stratified according to the 2008 WHO classification categories. Multilineage dysplasia and excess of blasts have a considerable impact on outcomes.