Myelodysplastic syndrome (MDS) is a heterogeneous disease of ineffective hemopoiesis with variable treatment outcome. Stratification of patients according to cytologic, cytogenetic, or cellular functional criteria does not consistently predict disease progression or treatment response. Improved prognostication would facilitate patient stratification and may ultimately lead to individualized patient treatment. We propose to explore the possibility that response to therapy and remission duration are determined, at least in part, by frequency and proliferative fraction of genetically aberrant cells in phenotypically-defined marrow stem cell compartments. We predict that MDS with stem cell involvement can be detected prior to therapy and that those patients with a low proliferative fraction of genetically aberrant stem cells will respond less well to chemotherapy than those with a high proliferative fraction. Furthermore, we postulate that remission duration is closely linked to the frequency of residual aberrant cells and their proliferative and clonogenic properties. We will test these hypotheses in a clinical trial of G-CSF and chemotherapy for high risk MDS by using flow cytometry and sorting, immunofluorescence-linked analyses of bromodeoxuridine incorporation into DNA, clonogenic assays and fluorescence in situ hybridization (FISH) to measure the proliferative fraction of genetically-aberrant stem cell subpopulations. Specifically, we will: 1)Determine whether the frequency and proliferative fraction of cytogenetically aberrant stem cells prognosticates for remission induction. 2) Determine whether remission duration correlates with the frequency-and proliferative fraction of genetically aberrant stem cells in remission marrow. 3) Determine whether the clonogenic potential of residual genetically aberrant cells prognosticates for remission duration. We anticipate that these data will prognosticate for treatment response and facilitate treatment monitoring in high risk MDS patients.
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