FLT3-TKD mutation in childhood acute myeloid leukemia.
Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.
Liang
D-C
DC
1Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
Shih
L-Y
LY
Hung
I-J
IJ
Yang
C-P
CP
Chen
S-H
SH
Jaing
T-H
TH
Liu
H-C
HC
Wang
L-Y
LY
Chang
W-H
WH
D000293:Adolescent; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D019089:Stem Cell Factor / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3
C107844:AML1-ETO fusion protein, human; D003062:Codon; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3