Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors.
FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835(+), 2 ITD(+)), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD(+), 2 D835(+)), 5 who were all originally ITD(+) had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease.
Kottaridis
Panagiotis D
PD
Department of Haematology, University College London, London, United Kingdom. p.kottaridis@ucl.ac.uk
Gale
Rosemary E
RE
Langabeer
Stephen E
SE
Frew
Marion E
ME
Bowen
David T
DT
Linch
David C
DC
D001483:Base Sequence; D001752:Blast Crisis / Q000235:genetics; D001854:Bone Marrow Cells / Q000473:pathology; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D011905:Genes, ras; D005819:Genetic Markers; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D018365:Neoplasm, Residual / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012008:Recurrence; D051941:fms-Like Tyrosine Kinase 3
D017931:DNA Primers; D004791:Enzyme Inhibitors; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3