title: Growth inhibition of AML cells with specific chromosome abnormalities by monoclonal antibodies to receptors for vascular endothelial growth factor.
abstract: By using neutralizing monoclonal antibodies to vascular endothelial growth factor receptor type 1 (VEGFR1) and VEGFR2, we have shown that acute myelogenous leukemia (AML) cells with specific chromosome abnormalities are dependent on VEGF/VEGFR system. AML with t(8;21) is the most dependent subtype on VEGF with both VEGFR1 and VEGFR2. t(15;17)AML cells depend on VEGF with VEGFR1. AML cells with 11q23 abnormalities showed variable dependence on VEGF. The growth of t(11;19)AML cells are most extensively inhibited by anti-VEGFR1 antibody. Then, the growth of Kasumi-1, a t(8;21) cell line was suppressed by either anti-VEGFR1 antibody (p=0.0022) or anti-VEGFR2 antibody (p=0.0029) in a dose-dependent manner. The growth of NB4, a t(15;17) cell line was more potently suppressed by anti-VEGFR1 antibody (p=0.0111) than by anti-VEGFR2 antibody (p=0.0477). These results are quite concordant with the results of clinical samples with t(8;21) or t(15;17). In addition, anti-VEGFR2 monoclonal antibody significantly potentiated the growth inhibitory effect of idarubicin for Kasumi-1. As for downstream signals, we have shown that VEGFR2 transduce growth and survival signals through phosphorylation of Akt and MEK in leukemia cells (Kasumi-1). However, VEGFR1 transduce growth and survival signals through pathways other than MEK and Akt (NB4), although Akt phosphorylation may account for some of the VEGFR1 signals (Kasumi-1). Finally, our data suggested that autocrine pathway of VEGF and VEGFRs observed in AML cells with specific chromosomal translocations have contributed to leukemogenesis as activated signaling of receptor tyrosine kinase.
authors.affiliation: Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Imai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miwa
authors.forename: Masato
authors.initials: M
authors.lastname: Shikami
authors.forename: Kazuto
authors.initials: K
authors.lastname: Suganuma
authors.forename: Mayuko
authors.initials: M
authors.lastname: Gotoh
authors.forename: Akihito
authors.initials: A
authors.lastname: Hiramatsu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Masaya
authors.initials: M
authors.lastname: Watarai
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hanamura
authors.forename: Akira
authors.initials: A
authors.lastname: Imamura
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Mihara
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nitta