Immune Dysregulation and Recurring Mutations in Myelodysplastic Syndromes Pathogenesis

Myelodysplastic syndromes (MDS) are clonal stem cell malignancies characterized by ineffective hematopoiesis leading to peripheral cytopenias and variable risk of progression to acute myeloid leukemia. Inflammation is associated with MDS pathogenesis. Several cytokines, reactive species of oxygen/nitrogen and growth factors are directly or indirectly involved in dysfunction of the MDS bone marrow (BM) microenvironment. Mutations in genes mainly regulating RNA splicing, DNA methylation and chromatin accessibility, transcription factors, signal transduction and the response to DNA damage contribute to ineffective hematopoiesis, genomic instability and MDS development. The inflammation-associated DNA damage in hematopoietic stem cells may also contribute to MDS development and progression with aggressive clinical characteristics. Many studies have aimed at clarifying mechanisms involved in the activity of immature myeloid cells as powerful modulators of the immune response and their correlation with aging, autoimmunity, and development of cancer. In this review, we explore recent advances and accumulating evidence uniting immune dysregulation, inflammaging and recurring mutations in the pathogenesis of MDS.