Myelodysplastic Neoplasms (MDS): Pathogenesis and Therapeutic Prospects

Abstract

Myelodysplastic neoplasms (MDS) are a group of hematological malignancies originating from hematopoietic stem cells (HSCs), characterized by distinct clinical and/or molecular heterogeneity across different MDS subtypes. This review elucidates the pathogenesis of MDS from two main perspectives: the bone marrow microenvironment and recurrent genetic abnormalities. Abnormal bone marrow microenvironment initiates aberrant innate immune response in HSCs, with quantitative and/or functional alterations of immune cells that collectively establish an immunosuppressive microenvironment, and abnormal bone marrow mesenchymal stromal cells that support and promote the progression of MDS. In addition, this review synthesizes current evidence on the biological functions and pathogenic mechanisms of frequently mutated genes in MDS. Furthermore, emerging therapies based on the pathogenesis of MDS are evaluated and summarized. In summary, aberrant innate immune responses promote pyroptosis of HSCs and acquisition of recurrent genetic abnormalities, resulting in the transformation of HSCs into MDS blasts; the immunosuppressive milieu (especially in higher-risk MDS) facilitates immune evasion of MDS blasts, ultimately leading to disease progression. Future research should focus on the interplay between different genetic abnormalities and immune dysregulation, coupled with the development of novel therapies targeting multiple nodes of the pathogenic network, to overcome current challenges in the treatment of MDS.

Keywords: bone marrow microenvironment; gene mutations; innate immunity; myelodysplastic neoplasms; myelodysplastic syndromes; therapeutic prospects.

Figure 1

Concise summary for MDS pathogenesis (Created in BioRender. Li, X. (2025) https://BioRender.com/tlr47gv). G-CSF: Granulocyte colony-stimulating factor; GM-CSF: Granulocyte-macrophage colony-stimulating factor; GSDMD: Gasdermin D; HSC: Hematopoietic stem cell; IL: Interleukin; IRAK: Interleukin-1 receptor associated kinase; MDSC: Myeloid-derived suppressor cell; MSC: Mesenchymal stromal cell; MyD88: myeloid differentiation factor 88; NF-κB: Nuclear factor-κB; NK cell: Natural killer cell; NOX: NADPH oxidase; SCF: Stem cell factor; SMAD: Mothers against decapentaplegic homolog; TIRAP: Toll-interleukin 1 receptor domain containing adaptor protein; TLR4: Toll-like receptor 4; TRAF6: Tumor necrosis factor receptor associated factor 6.

Figure 2

Partial novel therapies under clinical trials for MDS (Created in BioRender. Li, X. (2025) https://BioRender.com/104xdz1). MDSC: Myeloid-derived suppressor cell; NK cell: Natural killer cell.