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.
Highlights
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 demonstrate that primary healthy bone marrow- (BM) and MDS BM-derived CD34+ cells from lower-risk (International Prognostic Scoring System (IPSS) low- and intermediate 1) and higher-risk MDS, defined by the number of cytopenias, blast percentage in BM, and cytogenetic abnormalities, efficiently engraft in MISTRG mice and give rise to multi-lineage hematopoiesis and to myelo, erythro, and mekagaryopoiesis
We demonstrate that MDS patientderived MISTRG xenotransplants (MDS MISTRG patient-derived xenografts (PDX)) support the MDS stem cell across all MDS subtypes, replicate the patients’ MDS immunophenotype and dysplastic features, faithfully reproduce the clonal complexity of the disease at time of diagnosis and along disease progression, and are ideally suited for the testing of targeted therapeutics
Summary
Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Human cytokines provided by constitutive, transgene-driven expression in the NSG-SGM3 model (overexpressing human stem cell factor (SCF), granulocyte-monocyte-colony-stimulating factor (GMCSF), and interleukin-3 (IL3) from a cytomegalovirus promoter), improve myeloid differentiation and cellular proliferation, yet stem cell maintenance is impaired[11,12,13,14,15]. This limitation is overcome transiently by co-injection of autologous human MSCs16 or by creation of an ossicle from human MSCs that provides an improved human stem cell environment[17]. Given the high multilineage engraftment efficiency for normal and MDS HSCs and the histologic and clonal fidelity, MISTRG PDX represent a significant advancement over currently available xenotransplantation models and an ideal in vivo pre-clinical model for MDS
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