Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification

Scott A Armstrong, Andrew L Kung, Meghann E Mabon, Lewis B Silverman, Ronald W Stam, Monique L Den Boer, Rob Pieters, John H Kersey, Stephen E Sallan, Jonathan A Fletcher, Todd R Golub, James D Griffin, Stanley J Korsmeyer

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)173-83
Aantal pagina's11
TijdschriftCancer cell
Volume3
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - feb. 2003
Extern gepubliceerdJa

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