The broad long term of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with autoimmune disease. Our central hypothesis is that LGL leukemia results from dysregulated apoptosis. The goal of this proposal is to understand the mechanisms of treatment response in this model by pursuing correlative laboratory studies associated with an ECOG trial. Patients with neutropenia or anemia will initially receive oral methotrexate. Patients failing to respond to methotrexate will then receive oral cyclophosphamide. Samples from patients receiving cyclosporine on a CALGB study will also be evaluated.
Each specific aim will test a postulated mechanism of treatment efficacy:
Specific Aim 1 : To determine if treatment induces apoptosis in leukemic LGL;
Specific Aim 2 : To determine if treatment results in decreased secretion of Fas ligand;
Specific Aim 3 : To determine if treatment response is related to constitutive STAT signaling and regulation of STAT-responsive genes. Correlative studies in Specific Aim 1 include development of a predictive in vitro apoptotic assay and measurement of decoy Fas receptors on treatment. Mechanistic studies will investigate the mitochondrial-dependent apoptotic pathway induced by MTX. Correlative studies in Specific Aim 2 will measure levels of Fas ligand on treatment. Mechanistic studies will examine regulation of Fas ligand gene transcription. Correlative studies in Specific Aim 3 will measure levels of STAT activation and Mcl-1 protein expression on treatment. Treatment effects on expression of STAT-regulated genes will be examined using microarray analyses. Results of these studies should identify important molecular targets for drug development in hematologic malignancies.
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