The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.

Automated summary

Myelodysplastic neoplasm (MDS) is a diverse group of myeloid disorders that arise from hematopoietic stem cells and can progress to clonal hematopoiesis. MDS is characterized by an increased risk of transforming into acute myeloid leukemia (AML). Advances in next-generation sequencing (NGS) have revealed numerous recurrent mutations in genes such as FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1. The acquisition order of gene mutations during MDS progression to leukemia is non-random and has prognostic significance. Understanding the molecular events behind MDS transformation to AML has paved the way for targeted and personalized treatments.