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Myelodysplastic syndromes (MDS) are a group of hematological malignancies that manifest in hematopoietic stem cells and are caused by ineffective hematopoiesis.[1] Currently, MDS is defined as unexplained cytopenia combined with abnormalities in cell maturation leading to dysplastic features in >20% of myeloid cells.[2] MDS is one of the most frequently diagnosed malignancies in the United States and progresses to acute myeloid leukemia (AML) in 30% of patients.[2]
While the initiation of primary MDS is not well understood, research suggests that somatic DNA injury, defective DNA repair, impaired immunological responses, and dysfunctional cell signaling play an important role in early stage MDS development.[3] Like other malignancies, MDS is positively selected for through gene mutations[4] with the average MDS patient carrying nine somatic mutations, such as TET2, TP53, and RUNX1.[4, 5] These mutations may not directly drive MDS, however, evidence indicates that mutations to genes involved with DNA methylation and RNA splicing greatly contribute to dysregulation of genes critical to hematopoiesis, such as GATA1, KLF1, and HOXA9.[6]
MDS is classically characterized as hematopoietic stem cells (HSC) with clonal advantages due to somatic mutations or cellular dysfunction, discussed above. Studies have also identified the critical role of bone marrow microenvironments (BME) in MDS progression, particularly cytokine alterations and activities. Across several studies, high serum levels of TNF-α, TGF-β, IL-6, and IL-8[7] are present in MDS patient bone marrow (BM).[8] These proinflammatory molecules are typically associated with higher apoptotic rates, and in MDS patients, molecules such as TNF- α, correlate to poor MDS treatment performance.[7]
Furthermore, studies have also identified the critical role of malignant clones in MDS pathogenesis. Mesenchymal stromal cells (MSCs) are a key component of the bone marrow that regulate hematopoiesis and have immunomodulatory properties. In contrast, dysplastic MSCs in the bone marrow can create a microenvironment that supports clonal expansion of malignant cells. Dysplastic MSCs from MDS or AML patients have phenotypic abnormalities, including aberration in secreted proteins and cell surface protein expression, as well as increased senescence and decreased survival.[9,10] Disrupted methylation profiles are observed in both MDS malignant clones and MDS-MSCs. These methylation changes impact multiple signaling pathways which create a chronically inflamed BME that is harmful to normal HSCs and supports the expansion of MDS clones.[11]
While less understood, de novo MDS has been linked to chemotherapy, radiotherapy, and environmental carcinogens like benzene.[12] Therapy-related MDS (tMDS) is prevalent in 10-20% of patients 20 years after chemotherapy and/or radiation, and the World Health Organization (WHO) recognizes alkylating agents, like topoisomerase II inhibitors, as initiators of tMDS.[12] Due to the high incidence of MDS in elderly populations[13] with co-morbidities, treatment by bone marrow transplantation is often contraindicated and few therapeutic options exist.
Patients with MDS are typically divided into two different categories: low-risk MDS and high-risk MDS. The division of MDS into these two groups is useful for researchers and clinicians developing therapies for this highly heterogeneic disease.[14] Low-risk MDS therapies target symptoms of cytopenia through the use of erythropoiesis stimulating agents (ESA), such as epoetin alfa and darbepoetin alfa.[15] The Food and Drug Administration (FDA) has also approved two hypomethylating agents (HMAs), 5-azacitidine and decitabine, for use in patients with low-risk and high-risk MDS. While both standards of care noncompetitively inhibit DNA methyltransferase (DNMT1) and promote hypomethylation of DNA to block DNA synthesis,[16] 5-azacitidine integrates with RNA and interferes with ribosomal assembly to also limit tumor protein synthesis.[16, 17]
In 2023, the FDA and European Medicines Agency (EMA) also approved luspatercept, a recombinant fusion protein that enhances late-stage erythroblast differentiation, for low-risk MDS. Luspatercept indirectly moderates ineffective erythropoiesis by interacting with broad spectrum inhibitory signals, namely transforming growth factor-β (TGF- β) superfamily signaling.[18, 19] Downstream, signaling molecules, SMAD2 and SMAD3, negatively regulate TGF- β. Luspatercept works by binding to activin receptor type IIB on TGF- β which disrupts SMAD2 and SMAD3 signaling therefore improving erythropoiesis and boosting RBC production in MDS patients.[20, 21]
As our understanding of MDS pathophysiology improves, more effective treatment options will become available. Researchers are actively evaluating the toxicity of allogeneic hematopoietic stem cell transplantation, a therapy with curative potential.[19] Given the nature of such treatment which involves conditioning chemotherapy, the risk of aplasia and other graft-versus-host disease need to be adequately assessed. Additional studies, such as a newly announced Montefiore Einstein Comprehensive Cancer Center clinical trial,[22] are investigating new therapies to develop novel therapeutic strategies.
