Development Of a Preclinical Human Xenograft Model For Myelodysplastic Syndrome In Immunodeficient Mice Expressing Human Growth Factors

Myelodysplastic syndromes (MDS) are a diverse class of hematopoietic disorders, defined by progressive bone marrow failure, myeloid dysplasia, and an increased risk of acute myeloid leukemia (AML). The development of treatments for MDS has been hampered by the lack of an adequate in vivo model of disease. Mouse xenograft models for MDS have been challenging, as samples from patients with MDS have exhibited poor engraftment when transplanted into immunodeficient mice, with little evidence of persistent disease in recipient mice. Here, we tested a novel xenograft mouse model of MDS using an immunodeficient mouse strain that constitutively expresses human hematopoietic growth factors, SCF, GM-SCF and IL-3 (SGM3). These mice demonstrate improved engraftment of human hematopoietic cells from MDS patient samples. We have used bone marrow from patients diagnosed with MDS with blast counts ranging from 2-15% and differing cytogenetic profiles. Unfractionated bone marrow cells we injected into both NOD/LtSz-scid IL2RG^-/- (NSG) and NOD/LtSz-scid IL2RG^-/- SGM3 (NSGS) mice. These studies demonstrate significantly improved engraftment in the NSGS mice compared to NSG mice. Specifically, 1 out of 4 MDS patient samples demonstrated engraftment in NSG mice, but 3 out of 4 MDS samples demonstrated engraftment in NSGS mice. In NSG mice, we noted approximately 5-6% of human CD45+ cells in peripheral blood at 6 weeks after injection in one MDS sample, but subsequent to that, there was a drop to less than 1 percent of human CD45+ cells detected at 9 and 12 weeks post injection. The NSGS mice demonstrated more robust engraftment up to 15% human CD45+ cells in the peripheral blood at the 6 week time point in some samples, but subsequently fall to 1-2 % at 12 weeks post injection. This demonstrates that the NSGS strain of mice demonstrates improved xenograft efficiency of MDS bone marrow samples. Surprisingly, higher levels of blasts in the patient samples did not necessarily correspond to increased human CD45+ cell engraftment in the NSGS mice. This suggests the NSGS mice do model the MDS patient characteristics rather than overt leukemia. These results support our hypothesis that constitutive expression of human growth factors can promote engraftment of hematopoietic cells from patients with MDS. These studies will allow us to now use of this NSGS mouse model to test novel drug and/or immunotherapy approaches against human MDS in an in vivo mouse model system.