A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies

Yuanbin Song, Anthony Rongvaux, Ashley Taylor, Tingting Jiang, Toma Tebaldi, Kunthavai Balasubramanian, Arun Bagale, Yunus Kasim Terzi, Rana Gbyli, Xiaman Wang, Xiaoying Fu, Yimeng Gao, Jun Zhao, Nikolai Podoltsev, Mina Xu, Natalia Neparidze, Ellice Wong, Richard Torres, Emanuela M. Bruscia, Yuval Kluger, Markus G. Manz, Richard A. Flavell () and Stephanie Halene ()
Additional contact information
Yuanbin Song: Yale University School of Medicine
Anthony Rongvaux: Yale University School of Medicine
Ashley Taylor: Yale University School of Medicine
Tingting Jiang: Yale University School of Medicine
Toma Tebaldi: Yale University School of Medicine
Kunthavai Balasubramanian: Yale University School of Medicine
Arun Bagale: Yale University School of Medicine
Yunus Kasim Terzi: Yale University School of Medicine
Rana Gbyli: Yale University School of Medicine
Xiaman Wang: Yale University School of Medicine
Xiaoying Fu: Yale University School of Medicine
Yimeng Gao: Yale University School of Medicine
Jun Zhao: Yale University School of Medicine
Nikolai Podoltsev: Yale University School of Medicine
Mina Xu: Yale University School of Medicine
Natalia Neparidze: Yale University School of Medicine
Ellice Wong: VA Medical Center
Richard Torres: Yale University School of Medicine
Emanuela M. Bruscia: Yale University School of Medicine
Yuval Kluger: Yale University School of Medicine
Markus G. Manz: University Hospital and University of Zurich
Richard A. Flavell: Yale University School of Medicine
Stephanie Halene: Yale University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient “MISTRG” mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients’ dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample’s genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.

Date: 2019
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DOI: 10.1038/s41467-018-08166-x

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