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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1901-1908.
Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-06-1845.
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NEOPLASIA
Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia
Kazutaka Ozeki,
Hitoshi Kiyoi,
Yuka Hirose,
Masanori Iwai,
Manabu Ninomiya,
Yoshihisa Kodera,
Shuichi Miyawaki,
Kazutaka Kuriyama,
Chihiro Shimazaki,
Hideki Akiyama,
Miki Nishimura,
Toshiko Motoji,
Katsuji Shinagawa,
Akihiro Takeshita,
Ryuzo Ueda,
Ryuzo Ohno,
Nobuhiko Emi, and
Tomoki Naoe
From the Department of Infectious Diseases and the Department of Hematology, Nagoya University School of Medicine, Japan; the Department of Medicine, Japanese Red Cross Nagoya First Hospital; the Department of Medicine, Saiseikai Maebashi Hospital, Japan; the Research and Development Center for Higher Education, Nagasaki University, Japan; the Department of Hematology, Kyoto Prefectural University of Medicine, Japan; the Department of Hematology, Tokyo Metropolitan Komagome Hospital, Japan; the Second Department of Internal Medicine, Chiba University School of Medicine, Japan; the Department of Hematology, Tokyo Women's Medical University, Japan; the Second Department of Internal Medicine, Okayama University School of Medicine, Japan; the Department of Medicine III, Hamamatsu University School of Medicine, Japan; the Department of Internal Medicine and Molecular Science, Nagoya City University School of Medicine, Japan; and the Aichi Cancer Center, Nagoya, Japan.
Although FLT3 mutations are essentially found in myeloid-lineage leukemia cells, a high level of FLT3 expression was recently observed in MLL gene-rearranged acute lymphoblastic leukemia without FLT3 mutations. Here, we analyzed the biologic and clinical significance of the FLT3 transcript level in comparison with several gene alterations in 181 de novo acute myeloid leukemia (AML) cases. The mean expression level in AML was higher than that in normal mononuclear cells, whereas the range varied widely. A high level of FLT3 is related to internal tandem duplication of the FLT3 gene (FLT3/ITD), the mutations within the activation loop of FLT3 (FLT3/D835Mt), and tandem duplication of the MLL gene (MLL-TD) but not to p53 or N-RAS gene mutations. Furthermore, a high expression level in AML cases with FLT3 mutations was not related to MLL-TD. Overexpressed FLT3 revealed autophosphorylation and had the same sensitivity to the FLT3 inhibitor as FLT3/ITD. Overexpression of FLT3 (more than 200 000 copies/µgRNA) was an unfavorable prognostic factor for overall survival in 91 AML cases without FLT3/ITD. These results indicated that FLT3 overexpression may distinguish a novel disease entity in AML without FLT3 mutations and serve as a therapeutic target for FLT3 inhibitors.
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