Targeting inflammation in lower-risk MDS

The myelodysplastic syn dromes (MDS) are a het ero ge neous group of malig nant hema to poi etic stem cell dis or ders characterized by ineffective growth and differentiation of hematopoietic progenitors leading to peripheral blood cytopenias, dysplasia, and a variable risk of transformation to acute myelogenous leukemia. As most patients present with lower-risk disease, understanding the pathogenesis of ineffective hematopoiesis is important for developing therapies that will increase blood counts in patients with MDS. Various infl am ma tory cyto kines are ele vated in MDS and con trib ute to dysplastic differentiation. Inflammatory pathways mediated by interleukin (IL) 1b, IL-6, IL-1RAP, IL-8, and others lead to growth of aber rant MDS stem and pro gen i tors while inhibiting healthy hema to poi e sis. Spliceosome muta tions can lead to missplicing of genes such as IRAK4, CASP8 , and MAP3K , which lead to acti va tion of proinflammatory nuclear fac tor K B - driven path ways. Therapeutically, targeting of ligands of the transforming growth fac tor 13 (TGF - 13 ) path way has led to approval of luspatercept in transfusion-dependent patients with MDS. Presently, various clinical trials are evaluating inhib i tors of cyto kines and their recep tors in low - risk MDS. Taken together, an infl am ma tory micro en vi ron ment can support the pathogenesis of clonal hematopoiesis and low-risk MDS, and clinical trials are evaluating anti-inflammatory strategies in these diseases.

Automated summary

Myelodysplastic syndromes are malignant disorders of hematopoietic stem cells characterized by ineffective growth and differentiation, leading to low blood counts and a risk of leukemia. Understanding the pathogenesis of ineffective hematopoiesis is important for developing treatments for MDS.