Tandem duplications of MLL and FLT3 are correlated with poor prognoses in pediatric acute myeloid leukemia: a study of the Japanese childhood AML Cooperative Study Group.
BACKGROUND
Mixed-lineage leukemia (MLL)-partial tandem duplication (PTD) is associated with poor prognosis in adult acute myeloid leukemia (AML), but its relationship to pediatric AML is unknown.


METHODS
One hundred fifty-eight newly diagnosed AML patients, including 13 FAB-M3 and 10 Down syndrome (DS) patients, who were treated on the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed for MLL-PTD, as well as internal tandem duplication (ITD) and the kinase domain mutation (D835Mt) in the FLT3 gene.


RESULTS
We found MLL-PTD in 21 (13.3%) of 158 AML patients, but not in FAB-M3 or DS patients. The differences between patients with and without MLL-PTD were significant for 3-year overall survival (OS) (56.3% vs. 83.2%, P = 0.018), disease-free survival (DFS) (41.7% vs. 69.6%, P = 0.010), and relapse rate (RR) (54.3% vs. 27.6%, P = 0.0085) of 135 AML patients excluding the FAB-M3 and DS patients. Furthermore, ITD and D835Mt in the FLT3 gene were found in 17 (12.6%) and 8 (5.9%) of these 135 patients, respectively. The differences between patients with FLT3-ITD and the wild-type allele were significant for 3-year OS (35.3% and 84.3%, P < 0.0000001), DFS (40.0% and 66.9%, P < 0.003), and RR (52.4% and 30.3%, P < 0.005). Coduplication of both genes was found in only 3 (1.9%) patients.


CONCLUSIONS
AML patients with FLT3-ITD, but not D835Mt, showed a poor prognosis. AML patients with MLL-PTD were also correlated with poor prognosis in this study.
Shimada
Akira
A
Department of Hematology/Oncology, Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu, Shibukawa, Gunma 377-8577, Japan.
Taki
Tomohiko
T
Tabuchi
Ken
K
Taketani
Takeshi
T
Hanada
Ryoji
R
Tawa
Akio
A
Tsuchida
Masahiro
M
Horibe
Keizo
K
Tsukimoto
Ichiro
I
Hayashi
Yasuhide
Y
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000150:complications / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D008297:Male; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D011379:Prognosis; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3