Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia.
BACKGROUND
Recently, an internal tandem duplication of the FLT3 gene (FLT3/ITD) was found in 20% of adult cases of acute myelogenous leukemia (AML), and this length abnormality was suggested to be associated with leukemic progression.


METHODS
We examined the mRNA expression of the FLT3 gene by using reverse transcription-polymerase chain reaction (RT-PCR) in 64 children with AML, and further abnormal transcripts were cloned and sequenced.


RESULTS
An unexpected longer product was found in seven patients (11%) by RT-PCR of the FLT3 gene. Sequence analysis of these abnormal products revealed the presence of tandemly duplicated fragments in all seven patients. Three factors were identified to be associated with high incidence of FLT3/ITD; older patients (> or = 10 years) (P = 0.049), high WBC count (> or = 50,000/microl) at presentation (P = 0.002), and M3 in FAB subtypes (P = 0.002). Induction failure was observed in 3 (43%) of 7 patients with FLT3/ITD. Only FLT3/ITD was identified as a significant risk factor for induction failure by univariate analysis (P = 0.013), although it was not significant by multivariate analysis (P = 0.11). The Kaplan-Meier estimate of event-free survival rate at 5 years was 14% for patients with FLT3/ITD, which was significantly lower in comparison with 69% for patients without FLT3/ITD (P = 0.003). This finding was also identified by multivariate analysis (P = 0.01).


CONCLUSIONS
In this study, FLT3/ITD was observed in 11% of childhood AML and identified to be associated with poor prognosis. A large prospective study with uniform treatment is necessary to confirm our results.
Kondo
M
M
Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Japan.
Horibe
K
K
Takahashi
Y
Y
Matsumoto
K
K
Fukuda
M
M
Inaba
J
J
Kato
K
K
Kojima
S
S
Matsuyama
T
T
D000293:Adolescent; D000367:Age Factors; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D007958:Leukocyte Count; D008297:Male; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3