Dr Wei on the Effect of HMAs on Platelet Response and Megakaryocyte Maturation in MDS Mouse Models

"Using this mouse model, we determined that the main effect of HMAs in platelet response is through promoting late-stage megakaryocyte maturation and platelet production. That’s one of the most important findings that can help us pinpoint the major biological event that [the] HMA is affecting during this platelet response.”

Yue Wei, PhD, an assistant professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed how hypomethylating agents (HMAs) promote late-stage megakaryocyte maturation and platelet production in myelodysplastic syndrome (MDS) mouse models, according to data from a longitudinal analysis.

This analysis, results from which were presented at the 2025 ASH Annual Meeting, aimed to bridge the gap between clinical observations of platelet recovery and the underlying biological mechanisms that drive these improvements. Findings from the analysis showed that significant platelet count recovery typically manifests at approximately days 65 to 70 of treatment. Moreover, this response was observed only in the subset of patients harboring TET2 mutations who also presented with severe baseline thrombocytopenia, defined as a platelet count below 33 x 10⁹/L.

Although it is known that HMAs can improve platelet counts in early treatment cycles and have prognostic value, the exact cellular processes regulated by these agents remains unclear. Wei said. To address this area of uncertainty, Wei and colleagues utilized an MDS mouse model in their analysis. This model allowed researchers to simulate the disease environment and pinpoint the biological effects of HMA therapy that are difficult to observe in human patient samples.

Using this model, investigators determined that the primary mechanism by which HMAs induce a platelet response is through the promotion of late-stage megakaryocyte maturation and subsequent platelet production.

Such biological findings provide a cellular context for the clinical findings from this study, Wei said. She concluded by stating that identifying late-stage maturation as the key biological event affected by HMAs is a vital step toward understanding disease mechanisms and optimizing treatment for patients with high-risk MDS.

Disclosures: Wei had no financial relationships to disclose.