Luspatercept Targets Anemia Through a Unique Mechanism in a Mouse Model of Low-Risk MDS

By Blood Cancers Today Staff Writers - Last Updated: December 20, 2024

In a murine mitochondrial succinate dehydrogenase (SDH) knockdown model of low-risk myelodysplastic syndrome (MDS), luspatercept, a transforming growth factor β (TGF-β) ligand trap, alleviated anemia by promoting heme biosynthesis and enhancing erythroblast island (EBI) formation.

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Patients with MDS often present with burdensome anemia caused by ineffective erythropoiesis, for which standard treatments have shown limited efficacy. In previous analyses, Maiko Sezaki, PhD, University of Texas Health, San Antonio, and colleagues identified a subgroup of patients with MDS who presented with high TGF-β signaling and low mitochondrial complex II (MC II) or SDH gene expression. In this preclinical study, the researchers investigated the mechanism of SDH-mediated anemia using a doxycycline-inducible mouse model expressing short hairpin RNAs against SDH subunits in blood cells and whether this model mimics MDS pathogenesis. The restoration of the conditional SDH knockdown and pharmacologic intervention with luspatercept were studied.1

SDH knockdown reduced MC II activity, and the mice developed hallmark features of MDS, including pancytopenia, trilineage dysplasia, macrocytic anemia, increased iron overload, and impaired erythroid maturation. These findings supported the hypothesis that mitochondrial dysregulation and resultant pseudohypoxia play a role in MDS.

Restoring SDH expression (removing doxycycline) or luspatercept significantly relieved anemia in the SDH-deficient, MC II–reduced mice. Single-cell RNA sequencing revealed that luspatercept enhanced oxidative phosphorylation and amino acid biosynthetic pathways in erythroid progenitors. Luspatercept also expanded a population of macrophages expressing enhancing EBI-specific markers, such as EpoR and CD163, facilitating erythropoiesis by forming specialized niches within the bone marrow and spleen. Imaging and flow cytometry confirmed an increase in the number of active macrophages closely interacting with developing erythrocytes, suggesting a novel erythropoietin-independent mechanism of action. The therapeutic effect of luspatercept was further validated in a separate sickle cell anemia model, where it similarly relieved anemia and increased the formation of enhancing erythroblast islands.

These results suggest that TGF-β signaling-based changes in respiration, metabolic regulation, or both promote MDS pathogenesis and that targeting TGF-β with luspatercept reverses anemia by promoting heme biosynthesis and enhancing EBI formation. Further research is needed to evaluate luspatercept in combination regimens.

Reference

  1. Sezaki M, Yokoto A, Zhang X, et al. Luspatercept promotes heme biosynthesis and erythroblast island formation in a novel low-risk MDS mouse model. Abstract #877. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
Post Tags:ASH 2024: MDS
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