Cooperation between the partial tandem duplication of Mll (Mll PTD) and internal tandem duplication of FLT3 (FLT3 ITD) in the pathogenesis of acute myeloid leukemia AML
Advisor:Caligiuri, Michael A.
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Molecular Genetics Honors Theses; 2008
Acute myeloid leukemia (AML) with normal cytogenetics characterizes 40-50% of all acute leukemia cases . Previous studies have shown that the Fms-like tyrosine kinase-3 internal tandem duplication (FLT3 ITD) mutation is found in ~30% of patients with AML. Another mutation, known as the partial tandem duplication of the Mixed Lineage Leukemia gene (MLL PTD) is found in ~4-7% of AML patients with no other chromosomal disruptions. In a subgroup of patients harboring the MLL PTD, co-presence of the FLT3 ITD has also been found. Previously, we have generated and characterized the Mll PTD mouse model, and found that these mice live an essentially disease free life span with no signs of acute leukemia. Therefore, we wanted to determine whether the introduction of a second mutation such as the FLT3 ITD could cooperate with the Mll PTD to generate leukemia in a mouse model in order to better understand the pathogenesis of this disease. Indeed we found that the combination of MLL PTD and FLT3 ITD induces leukemia in our mouse model between 35-65 weeks of age in 100% of the mice analyzed thus far. Understanding how the FLT3 cooperates with the Mll PTD in leukemic transformation will,hopefully identify novel pathways that could be used to identify new strategies to selectively target these leukemia cells in AML patients.
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