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

Cancer Cell. 2003 Feb;3(2):173-83. doi: 10.1016/s1535-6108(03)00003-5.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Annexin A5 / metabolism
  • Antineoplastic Agents / pharmacology*
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression
  • Histone-Lysine N-Methyltransferase
  • Humans
  • In Situ Hybridization, Fluorescence
  • Interleukin-3 / metabolism
  • Mice
  • Myeloid-Lymphoid Leukemia Protein
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Protein Kinase C / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogenes*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Staurosporine / analogs & derivatives*
  • Staurosporine / pharmacology*
  • Transcription Factors*
  • Transfection
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3


  • Annexin A5
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Interleukin-3
  • KMT2A protein, human
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • FLT3 protein, human
  • Flt3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Protein Kinase C
  • Staurosporine
  • midostaurin