Development and Characterization of a Novel Human Xenograft Model Using an MDS Patient-Derived Cell Line

Abstract 3814

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, defined by ineffective hematopoiesis, blood cytopenias, myeloid dysplasia, and an increased risk of acute myeloid leukemia (AML). Immunodeficient mice engineered to support human tumor xenografts represent a pivotal development in the study of human cancers. The xenograft model has been an attractive approach to interrogate human AML; in contrast, MDS patient samples exhibit negligible or poor engraftment, with no evidence of disease in immunocompromised recipient mice. To circumvent this limitation we developed a novel xenograft mouse model using an MDS cell line, MDSL. The MDSL cell line was derived from the non-leukemic phase of an MDS patient with refractory anemia-ringer sideroblasts, and has maintained growth-factor dependence and sensitivity to Lenalidomide. Two immunocomprismised mouse stains were used for xenotransplantation of MDSL cell: NOD/LtSz-scid IL2RG (NSG) and NOD/LtSz-scid IL2RG-SGM3 (NSGS). NSGS mice are identical to NSG except that they have been engineered to express three human cytokines, SCF, GM-CSF and IL-3, to improve engraftment of human hematopoietic cells. Following transplantation of MDSL cells by either intrafemoral or intravenous injection, NSG and NSGS animals exhibited human cell grafts in the bone marrow, peripheral blood, and spleen. Subsequently, mice developed a fatal disease exhibiting features of human MDS, including anemia and thrombocytopenia, which coincides with clonal expansion and increased human cell graft in all hematopoietic organs. The median survival for NSGS and NSG mice was 21 and 55 days post-injection, respectively. The shortened latency in NSGS mice suggests that the expression of human cytokines accelerates the growth and enhances survival of the MDSL cells in vivo. MDSL cells isolated from the bone marrow of primary recipient mice were capable of initiating an MDS-like disease in secondary recipients. Given that few preclinical options for MDS are available, we also evaluated whether this model is suitable for therapeutic studies. Since MDSL cells are sensitive to Lenalidomide and IRAK1 Inhibitor (Rhyasen et al, ASH 2011), we evaluated the effects of these drugs in the xenograft model. After xenotransplantation of MDSL cells, NSGS mice were administered either Lenalidomide or IRAK1 Inhibitor. Our preliminary findings indicate that mice xenografted with MDSL cells are amenable to drug delivery and show a response to treatment. In summary this work describes a novel xenograft model of human MDS, the first to develop clinical features resembling human disease. In addition, we predict that this model will also be useful for preclinical studies to examine novel and existing MDS therapies.