A Mouse Model of Myelodysplastic Syndrome Progression

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DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is a fatal hematopoietic clonal disorder with the highest incidence among older people (>60 years). MDS is a complex disease characterized by apparently contradictory coexisting features. The patients have insufficient erythropoiesis and severe pancytopenia. At the same time, their BM is hypercellular with low blast counts and trilineage differentiation. Some patients develop symptoms that can be managed with maintenance therapy and have reasonably long survival before progressing to the acute phase (AML) of the disease. Others can be managed only with blood transfusions. Once the disease progresses to AML, the prognosis is poor with short survival. As the age of the population increases, the incidence of MDS becomes more frequent and its role in limiting life expectancy becomes more prominent. The genetic bases of MDS are not known. Because BM apoptosis is seen in MDS, it is thought that BM replicative senescence or inability to respond to growth factors could contribute to the disease. Partial deletion and loss of chromosome 5 and/or 7 are recurring aberrations in MDS but the genes that are deleted remain unidentified. A more informative abnormality is the rearrangement of chromosome 3 band q26 seen in about 10% of MDS. This region contains EVI1, a gene not detected in normal BM but inappropriately activated in MDS by the rearrangement. EVI1-positive MDS patients develop fatal hematopoietic defects rapidly evolving to AML and in general their survival is less than one year. Until very recently, there was no cell line or animal model for MDS. Therefore, the progress in understanding this disease and testing potential treatments has been extremely slow. Very recently, we have developed the first murine model of MDS by bone marrow infection with an EVI1-expressing retrovirus and transplantation into syngeneic recipients. The reconstituted mice invariably succumb to a fatal disease that has several characteristics of MDS, including BM hypercellularity, impaired erythropoiesis and anemia, thrombocytopenia, very low blood counts, and apoptosis in hematopoietic organs. Preliminary studies with this model have provided clear clues about hematopoietic and cell cycling pathways affected by EVIL These effects occur in BM immediately after expression of EVIL Because the EVIl-positive mice succumb 10-12 months after transplantation, it appears that these effects are not fatal, suggesting that additional events must irreversibly damage the hematopoietic organs leading to death. MDS does not progress to AML in these mice. Therefore this model is ideal to understand the disease when is still potentially treatable. Based on these preliminary results, we propose that the forced expression of EVI1 induces a fatal hematopoietic disease in mice that resembles human MDS. The disease progresses from a viable early stage in which the erythropoietic lineage is compromised, to a fatal late stage in which hematopoietic cells undergo apoptosis and do not respond to growth factors. In this stage, blood counts sharply drop, and multi-lineage defects appear, leading to death. The goals of this proposal are to further evaluate the role of EVI1 in the disease and understand the transition between the first (viable) stage and the second (fatal) stage, with the intent of identifying suitable targets for drugs development. We plan to use a combination of molecular biology and in vivo systems to dissect the molecular pathways of EVI1 and identify steps that can be used for the development of new treatments.