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Blood, 15 January 2005, Vol. 105, No. 2, pp. 812-820.
Prepublished online as a Blood First Edition Paper on September 16, 2004; DOI 10.1182/blood-2004-06-2498.
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NEOPLASIA
FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression
Patrick Brown,
Mark Levis,
Sheila Shurtleff,
Dario Campana,
James Downing, and
Donald Small
From the Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; Departments of Pathology and Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN; and University of Tennessee College of Medicine, Memphis, TN.
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.
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