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Tandem duplication of the FLT3 gene in acute lymphoblastic leukemia: a marker for the monitoring of minimal residual disease

Leukemia volume 14, pages 522–524 (2000)Cite this article

Fms-like tyrosine kinase 3 (FLT3), also referred as to FLK2 or STK-1, is a member of the class III receptor tyrosine kinase (RTK) family, along with KIT, FMS and PDGFR. Binding of its natural ligand induces FLT3 dimerization and consecutive tyrosine kinase activation and autophosphorylation. This signal transduction cascade plays an important role in growth control of pluripotent hematopoietic cells, early progenitor cells and immature lymphocytes. The structure of FLT3 is composed of five immunoglobulin-like subdomains in the extracellular region, a single transmembrane (TM) and a juxtamembrane (JM) domain, two intracellular tyrosine kinase domains (TK1 and TK2) separated by a kinase insert domain and a C-terminal domain.

An internal tandem duplication of the FLT3 gene (FLT3/ITD) has been discovered in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with frequencies of 20% and 3–15%, respectively.12 The FLT3/ITD is restricted to the JM/TK1 domains corresponding to exon 11–12 and is occasionally accompanied by the insertion of a few nucleotides. The FLT3/ITD is a somatic event since no mutation was found in normal hematopoietic cells or matched remission samples of AML patients harboring FLT3/ITD.1 Interestingly, FLT3/ITD occurs in-frame and could therefore encode an altered FLT3 receptor.1 The function of FLT3/ITD has not been fully elucidated. A recent study demonstrated that elongation of the JM domain causes ligand-independent dimerization of the mutant FLT3 receptor, resulting in a constitutive activation.3 The authors assumed that a DNA-replication error could generate FLT3/ITD. Apart from AML patients, Xu et al4 reported on an FLT3/ITD in two ALL patients. We therefore searched for FLT3/ITD upon polymerase chain reaction (PCR) analysis in 174 children with ALL. Moreover, we describe that FLT3/ITD can be used as marker for the detection of minimal residual disease (MRD).

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References

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Acknowledgements

The authers are grateful to the participants of the BFM study group for continuous support and to Prof WD Ludwig for immunophenotype analysis. M Nakao is a recipient of a fellowship from the Alexander von Humboldt-Stiftung. This work was supported by a grant from the Deutsche Krebshilfe to CRB.

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Authors and Affiliations

  1. Institute of Human Genetics, University of Heidelberg, Germany

    M Nakao, JWW Janssen, D Erz & CR Bartram

  2. Department of Internal Medicine III, Kyoto Prefectural University of Medicine, Japan

    T Seriu

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Nakao, M., Janssen, J., Erz, D. et al. Tandem duplication of the FLT3 gene in acute lymphoblastic leukemia: a marker for the monitoring of minimal residual disease. Leukemia 14, 522–524 (2000). https://doi.org/10.1038/sj.leu.2401695

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