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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. This Article Full Text (PDF) All Versions of this Article: 2004-06-2498v1 105/2/812    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Brown, P. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Brown, P. Articles by Small, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 8, 2004 Accepted August 31, 2004 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* Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Baltimore, MD, USA; Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Baltimore, MD, USA Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee College of Medicine, Memphis, TN, USA Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee College of Medicine, Memphis, TN, USA * Corresponding author; email: donsmall{at}jhmi.edu. 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 LMLL-rearranged and 28% of hyperdiploid ALL. We determined the anti-leukemic 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 to samples with low levels of expression (8%, N=13, p=0.0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, N=11, p=0.00058), high hyperdiploidy (100%, N=5, p=0.0007), and/or FLT3 mutations (100%, N=4, p=0.0021). 7 of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701, while 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: On target for advances in the treatment of childhood acute lymphoblastic leukemia William L. Carroll Blood 2005 105: 438-439. [Full Text] [PDF] This article has been cited by other articles: R. K. 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