Prognostic implications of Flt3 mutations in AML

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DESCRIPTION (provided by applicant): Activating mutations in the Flt3 receptor gene are the most common somatic mutation in AML and cause constitutive activation of the Flt3 receptor tyrosine kinase. Presence of these mutations (Flt3 internal tandem duplication, FIt3/ITD and Flt3 point mutations, FIt3/PM) may lead to lower rate of remission induction and increased rate of relapse. The aim of this project is to evaluate diagnostic marrow specimens from pediatric and adult AML patients treated on national multi-institutional trials (CCG, POG and SWOG) for Flt3 activating mutations and to correlate FLT3 mutations with other biologic markers. Initially, presence of Flt3 activating mutations will be determined and correlated with clinical characteristics and outcome in an attempt to define the prognostic significance of these mutations. Clinical significance of the FIt3/ITD mutations will further be characterized by determination of the ITD allelic ratio and Loss of Heterozygosity (LOH) of Chromosome 13. We have created a collaborative network with our pediatric and adult colleagues where the information generated on Flt3 activating mutations will be merged and correlated with the data on c-kit activating mutations, minimal residual disease and RNA expression profile in order to better define the biology of this mutation. We will also perform Flt3 mutational analysis as a part of national phase III AML trials in Adults (SWOG SO106) and pediatrics (COG AML trial- under development) in a prospective fashion to determine whether therapy intensification would alter the prognostic significance of Flt3 mutations. This grant project will undertake an extensive evaluation of Flt3 mutations in the largest patient population tested to date and will correlate the data with other biologic markers.