[Predisposition and progression of myelodysplastic syndromes]

Recent advances in sequencing technologies have increased the detection rate for identifying germline mutations that predispose an individual to various myeloid neoplasms and somatic mutations acquired during progression from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML). In addition to pediatric subjects, adult patients were analyzed in order to obtain a complete spectrum of driver mutations in germline cells and/or somatic tumor samples. As shown in several recent studies, such driver mutations are acquired in a gene-specific fashion. DDX41 mutations are observed in germline cells long before MDS presentation. SAMD9/SAMD9L germline mutations associated with defective hematopoiesis account for recurrent and familial -7/del (7q) lesions, which result in the removal of the disadvantageous allele. Additionally, MDS cases in younger population display compound heterozygous germline mutations in the Shwachman-Diamond syndrome-associated SBDS gene. In peripheral blood samples from healthy elderly individuals, DNMT3A, TET2, and ASXL1 somatic mutations are usually detected due to age-related clonal hematopoiesis and are considered to be a risk factor for hematological neoplasms. In MDS, mutations of genes, such as NRAS and FLT3, designated as type-1 genes, are significantly associated with leukemic evolution. On the other hand, mutations in type-2 genes, including RUNX1 and GATA2, are related to progression from low risk MDS to high risk MDS.