FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression.
FMS-like tyrosine kinase 3 (FLT3) is almost universally expressed in B-precursor childhood acute lymphoblastic leukemia (ALL). Cases of ALL with MLL gene rearrangements and those with high hyperdiploidy (> 50 chromosomes) express the highest levels of FLT3, and activating mutations of FLT3 occur in 18% of MLL-rearranged and 28% of hyperdiploid ALL cases. We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. CEP-701 induced pronounced apoptotic responses in a higher percentage of samples that expressed high levels of FLT3 (74%, n = 23) compared with samples with low levels of expression (8%, n = 13; P = .0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, n = 11; P = .0005), high hyperdiploidy (100%, n = 5; P = .0007), and/or FLT3 mutations (100%, n = 4; P = .0021). Seven of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701, whereas 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. We conclude that the FLT3 inhibitor CEP-701 effectively suppresses FLT3-driven leukemic cell survival. Clinical testing of CEP-701 as a novel molecularly targeted agent for the treatment of childhood ALL is warranted.
Brown
Patrick
P
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
Levis
Mark
M
Shurtleff
Sheila
S
Campana
Dario
D
Downing
James
J
Small
Donald
D
D000367:Age Factors; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007223:Infant; D051788:Myeloid-Lymphoid Leukemia Protein; D010641:Phenotype; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
D002227:Carbazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005663:Furans; D007211:Indoles; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C119379:lestaurtinib; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3