title: Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.
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.
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Meghann E
authors.initials: ME
authors.lastname: Mabon
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Stam
authors.forename: Monique L
authors.initials: ML
authors.lastname: Den Boer
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: John H
authors.initials: JH
authors.lastname: Kersey
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007377:Interleukin-3; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin