Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia.
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/microgRNA) 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.
Ozeki
Kazutaka
K
Department of Infectious Diseases, Nagoya University School of Medicine, Japan.
Kiyoi
Hitoshi
H
Hirose
Yuka
Y
Iwai
Masanori
M
Ninomiya
Manabu
M
Kodera
Yoshihisa
Y
Miyawaki
Shuichi
S
Kuriyama
Kazutaka
K
Shimazaki
Chihiro
C
Akiyama
Hideki
H
Nishimura
Miki
M
Motoji
Toshiko
T
Shinagawa
Katsuji
K
Takeshita
Akihiro
A
Ueda
Ryuzo
R
Ohno
Ryuzo
R
Emi
Nobuhiko
N
Naoe
Tomoki
T
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020440:Gene Duplication; D016158:Genes, p53; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014443:Tyrosine; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3