A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia

Karsten Spiekermann; Ksenia Bagrintseva; Claudia Schoch; Torsten Haferlach; Wolfgang Hiddemann; Susanne Schnittger

doi:10.1182/blood-2002-03-0953

A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia

Blood. 2002 Nov 1;100(9):3423-5. doi: 10.1182/blood-2002-03-0953.

Authors

Karsten Spiekermann¹, Ksenia Bagrintseva, Claudia Schoch, Torsten Haferlach, Wolfgang Hiddemann, Susanne Schnittger

Affiliation

¹ 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

PMID: 12384447
DOI: 10.1182/blood-2002-03-0953

Abstract

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Cell Division / drug effects
Codon / genetics
DNA Mutational Analysis
Enzyme Inhibitors / pharmacology
Exons / genetics*
Fatal Outcome
Female
Gene Expression Regulation, Leukemic / genetics*
Humans
Indoles / pharmacology
Interleukin-3 / pharmacology
Leukemia, Erythroblastic, Acute / genetics*
Leukemia, Myeloid, Acute / genetics*
Male
Mice
Mutagenesis, Insertional*
Neoplasm Proteins / genetics*
Phosphorylation
Phosphotyrosine / analysis
Protein Processing, Post-Translational
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured / drug effects
fms-Like Tyrosine Kinase 3

Substances

Codon
Enzyme Inhibitors
Indoles
Interleukin-3
Neoplasm Proteins
Proto-Oncogene Proteins
SU 5614
Phosphotyrosine
FLT3 protein, human
Flt3 protein, mouse
Receptor Protein-Tyrosine Kinases
fms-Like Tyrosine Kinase 3