Abstract
Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.
Highlights
Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by bone marrow (BM) dysplasia, cytopenias, recurrent genomic aberrations, and a predisposition for progression to acute myeloid leukemia [1]
Robust long-term engraftment in an MDS patient-derived xenograft (PDX) model enables comprehensive preclinical substance testing and molecular readouts in vivo In the current study, we performed an evaluation of whether our previously established MDS PDX model could be used as a preclinical platform to perform MDS patient–individual substance testing
This did not influence the overall notion of stable clonal composition in both conditions, which was further corroborated by comparable overall stable dynamics of the deltaVAFs (Figs. 2I and 6F, J, and Supplementary Fig. S8F, Q, X). Tpo receptor agonists such as EPAG have been approved as efficacious and well-tolerated drugs for non-malignant disorders associated with thrombocytopenia, as well as severe aplastic anemia
Summary
Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by bone marrow (BM) dysplasia, cytopenias, recurrent genomic aberrations, and a predisposition for progression to acute myeloid leukemia [1]. There has been great progress in the molecular characterization of MDS [2], the translation of this mutational data into novel treatment strategies is frequently impeded by a lack of preclinical models to address functional questions. To overcome these limitations, we have previously established a niche-based patient-derived xenograft (PDX) model in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice consisting of an orthotopic co-transplantation of ex vivo expanded BM-derived mesenchymal stroma cells (MSCs) and CD34+ hematopoietic stem cells [3]. Many MDS patients are dependent on supportive platelet (PLT) transfusions, which in turn are associated with considerable risks [7, 11]
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