A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia.
Activating length mutations in the juxtamembrane (JM) domain of the FLT3 gene (FLT3-LM) and mutations in the catalytic domain (FLT3D835/836) of this receptor tyrosine kinase represent the most frequent genetic alterations in acute myeloid leukemia (AML). Here, we describe a 6-bp insertion in the activation loop of FLT3 between codons 840 and 841 of FLT3 (FLT3-840GS) in 2 unrelated patients with AML. Screening for other activating mutations of FLT3, KIT, and NRAS showed no further genetic alterations in patients carrying the FLT3-840GS. In functional analyses we could show that this mutant is hyperphosphorylated on tyrosine and confers interleukin 3-independent growth to Ba/F3 cells, which can be inhibited by a specific FLT3 protein tyrosine kinase (PTK) inhibitor. Our results show for the first time that in addition to known mutations in the JM and the catalytic domain, further activating length mutations exist in the FLT3 gene.
Spiekermann
Karsten
K
Clinical Cooperative Group Leukemia, GSF, National Research Center for Environment and Health, University Hospital Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, 81377 Munich, Germany. spiekermann@gsf.de
Bagrintseva
Ksenia
K
Schoch
Claudia
C
Haferlach
Torsten
T
Hiddemann
Wolfgang
W
Schnittger
Susanne
S
D000368:Aged; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D051379:Mice; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3
D003062:Codon; D004791:Enzyme Inhibitors; D007211:Indoles; D007377:Interleukin-3; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C416849:SU 5614; D019000:Phosphotyrosine; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3