Myelodysplastic syndromes: Updates on Genomic Landscape, Molecular Subtypes, & Targeted Therapies

Advances in modern molecular and genomic testing have spurred tremendous progress in our understanding of MDS pathogenesis. Here we review common diagnostic methods, the evolving multi-omics landscape of MDS, molecular subtypes, and targeted therapies.

MDS is a heterogeneous disease defined by a wide array of chromosomal abnormalities and > 40 common somatic mutations affecting RNA splicing complex, chromatin modification, DNA methylation, lineage specific transcription, DNA damage, RAS/MAPK signaling, and cohesin complex pathways. This has shaped current WHO/ICC classification criteria with the inclusion of 3 genetically defined subgroups: del(5q), SF3B1, and TP53-mutated. IDH1/2-mutated MDS is a new, emerging subgroup, for which multiple clinical trials are underway. Several recent targeted drug approvals including luspatercept and imetelstat have greatly expanded the treatment arsenal for lower-risk MDS. Standard of care therapy options for high-risk MDS, in particular TP53-mutated, remain limited beyond HMAs and transplant and are an active area of investigation.