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Nat Commun. 2019 Jan 21;10(1):366. doi: 10.1038/s41467-018-08166-x.

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

Author information

1
Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
3
Fred Hutchinson Cancer Research Center, Program in Immunology, Clinical Research Division, and Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
5
Laboratory of Translational Genomics, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
6
University of New Haven, New Haven, CT, USA.
7
Department of Medical Genetics, Faculty of Medicine, Baskent University, Ankara, Turkey.
8
Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
9
Department of Laboratory Medicine, Shenzhen Children's Hospital, Shenzhen, People's Republic of China.
10
Section of Hematology/Oncology, VA Medical Center, West Haven, CT, USA.
11
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
12
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
13
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
14
Program of Applied Mathematics, Yale University, New Haven, CT, USA.
15
Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
16
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. richard.flavell@yale.edu.
17
Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. richard.flavell@yale.edu.
18
Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA. stephanie.halene@yale.edu.

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.

PMID:
30664659
PMCID:
PMC6341122
DOI:
10.1038/s41467-018-08166-x
[Indexed for MEDLINE]
Free PMC Article

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