Pathogenesis and treatment of immune dysregulation associated with myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are a clonal disorder based on genomic mutations in hematopoietic stem cells. They are categorized as lower-risk MDS, characterized by peripheral cytopenia; and higher-risk MDS, characterized by progression to acute myeloid leukemia. Previous studies reported that inflammation and immune activation are deeply involved in the pathogenesis of lower-risk MDS. Recent studies elucidated the molecular basis for the activation of inflammatory pathways via dysregulated innate immune system and the resultant cell-death acceleration in lower-risk MDS. Conversely, immunosuppression and immune escape are substantially involved in the pathogenesis and disease progression of higher-risk MDS. VEXAS syndrome is an autoinflammatory disease characterized by clonal hematopoiesis with somatic mutation of UBA1 in hematopoietic stem and progenitor cells and has attracted broad attention as a lower-risk MDS model caused by systemic inflammation. Although therapeutic effects of immunosuppressants are observed for a limited number of patients with lower-risk MDS with inflammation, an optimal treatment should be developed based on their pathology.