Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, Pieters R, Kersey JH, Sallan SE, Fletcher JA, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173–83.
NOTES
Armstrong, Scott AKung, Andrew LMabon, Meghann ESilverman, Lewis BStam, Ronald WDen Boer, Monique LPieters, RobKersey, John HSallan, Stephen EFletcher, Jonathan AGolub, Todd RGriffin, James DKorsmeyer, Stanley JengK08 CA 92551/CA/NCI NIH HHS/P01 CA 68484/CA/NCI NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.Cancer Cell. 2003 Feb;3(2):173-83. doi: 10.1016/s1535-6108(03)00003-5.
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.
Last updated on 02/17/2021