A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies

Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. We developed a novel MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG"...

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Main Authors Song, Yuanbin, Rongvaux, Anthony, Taylor, Ashley, Jiang, Tingting, Toma Tebaldi, Balasubramanian, Kunthavai, Bagale, Arun, Terzi, Yunus K, Rana Gbyli, Wang, Xiaman, Zhao, Jun, Podoltsev, Nikolai, Xu, Mina, Neparidze, Natalia, Wong, Ellice, Torres, Richard, Bruscia, Emanuela M, Kluger, Yuval, Manz, Markus G, Flavell, Richard A, Halene, Stephanie
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.02.2018
Cold Spring Harbor Laboratory
Edition1.1
Subjects
Cancer Biology
Cytotoxicity
Hematopoietic stem cells
Immunodeficiency
Myelodysplastic syndrome
Stem cell transplantation
Stem cells
Xenografts
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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. We developed a novel MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice that for the first time 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.
AbstractList Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. We developed a novel MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice that for the first time 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.
Author Song, Yuanbin
Balasubramanian, Kunthavai
Flavell, Richard A
Kluger, Yuval
Bagale, Arun
Neparidze, Natalia
Podoltsev, Nikolai
Bruscia, Emanuela M
Manz, Markus G
Jiang, Tingting
Toma Tebaldi
Torres, Richard
Wong, Ellice
Rongvaux, Anthony
Terzi, Yunus K
Wang, Xiaman
Zhao, Jun
Halene, Stephanie
Taylor, Ashley
Xu, Mina
Rana Gbyli
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Snippet Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current...
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proquest
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SubjectTerms Cancer Biology
Cytotoxicity
Hematopoietic stem cells
Immunodeficiency
Myelodysplastic syndrome
Stem cell transplantation
Stem cells
Xenografts
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Title A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies
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https://www.biorxiv.org/content/10.1101/265082
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