Examination of FLT3 Mutations in Acute Myeloid Leukemia

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DESCRIPTION (provided by applicant): Dr. Stirewalt's long-term objective is to develop treatments for patients with AML that will reduce morbidity and improve survival. Over the next five years, Dr. Stirewalt will perform pre- clinical and clinical studies that examine the effects of FLT3 mutations in AML. Specific Aim I: Examine the clinical significance of FLT3 mutations in previously untreated adult patients with AML. The prognostic significance of FLT3 mutations in adults with AML remains uncertain. Specific Aim I prospectively examines the clinical significance of FLT3 mutations in adult AML patients assigned to SWOG SOl06, a phase III trial consisting of standard dose induction and high dose Ara-C consolidation followed by randomization to observation or Mylotarg. AML patients will be screened for FLT3 mutations using sensitive PCR/SSCP assays. Mutation data will be correlated with clinical outcomes. We hypothesize that FLT3 ITDs will be an independent negative prognostic factor in adult patients with AML. Specific Aim II: Examine the ability of PCR assays for FLT3 ITDs to predict clinical relapse. Approximately 90 percent of FLT3 ITDs occur in patients without a molecular marker for MRD, and we have developed sensitive PCR assays for FLT3 ITDs that may be used as tests for MRD. Specific Aim II examines the ability of MRD assays for FLT3 ITDs to predict clinical relapse in patients on SWOG S0106. The MRD assays for FLT3 ITDs will be performed in all FLT3 positive patients at specific time points during their treatment and results will be correlated with clinical outcomes. We hypothesize that MRD assays using FLT3 ITDs will be predictive of clinical relapse. Specific Aim III: Examine the molecular effectors involved in the activation of mutated FLT3 receptors and develop techniques to counteract the effects of mutated FLT receptors. Data from murine cells with transfected FLT3 ITDs suggest that FLT3 ITDs result in activation of the FL T3 receptors that can be inhibited by nonspecific tyrosine kinase inhibitors. We will transfact genetically engineered FL T3 mutations into murine cells. The effects of these FLT3 mutations on activation of the receptor, MAP kinase, STAT 3&5, c- Jun, and global genetic expression will be examined. We will also determine if antibodies directed against the FL T3 receptor, novel tyrosine kinese inhibitors, and/or non-receptor tyrosine kinase inhibitors can alter the effects of FLT3 mutations. Parallel experiments using patient AML samples with FLT3 ITDs will also be performed. We hypothesize that FLT3 ITDs will premote constitutive activation of the receptor that can be blocked by tyrosine kinase inhibitors. In addition to the research proposal, Dr. Stirewalt has developed an educational program that includes specific training objectives, didactic courses, and formal reviews by his advisors. This educational program will strengthen his background in clinical trial design and methodology. Together, the research proposal and educational program provide Dc Stirewalt with the skills to become an independent clinical investigator.