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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1085-1088.
Prepublished online as a Blood First Edition Paper on September 22, 2003; DOI 10.1182/blood-2003-02-0418.
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NEOPLASIA
Brief report
FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy
Takeshi Taketani,
Tomohiko Taki,
Kanji Sugita,
Yoshiyuki Furuichi,
Eiichi Ishii,
Ryoji Hanada,
Masahiro Tsuchida,
Kenichi Sugita,
Kohmei Ida, and
Yasuhide Hayashi
From the Department of Pediatrics, Graduate School of Medicine, University of Tokyo; Department of Pediatrics, Shimane Medical University; Department of Pediatrics, Faculty of Medicine, University of Yamanashi; Department of Pediatrics, Faculty of Medicine, Saga University; Division of Hematology/Oncology, Saitama Children's Medical Center; Department of Pediatrics, Ibaraki Children's Hospital; Division of Hematology, Department of Pediatrics, Dokkyo University School of Medicine, Tochigi; and Gunma Children's Medical Center, Japan.
Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2APBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy. (Blood. 2004;103:1085-1088)
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