Author/Authors :
Armstrong، نويسنده , , Scott A and Kung، نويسنده , , Andrew L and Mabon، نويسنده , , Meghann E and Silverman، نويسنده , , Lewis B and Stam، نويسنده , , Ronald W and Den Boer، نويسنده , , Monique L and Pieters، نويسنده , , Rob and Kersey، نويسنده , , John H and Sallan، نويسنده , , Stephen E and Fletcher، نويسنده , , Jonathan A and Golub، نويسنده , , Todd R and Griffin، نويسنده , , James D and Korsmeyer، نويسنده , , Stanley J، نويسنده ,
Abstract :
We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.
