Internal tandem duplications in the Flt3-gene in human acute myeloid leukemia

In the process of hematopoietic development errors may occur, resulting in the aber¬rant activation of (proto-)oncogenes and inactivation of tumor-suppressor genes. This aberrant gene expression may finally result in leukemia, a neoplastic disorder in which immature hematopoietic cells accumulate in the BM where they fail to fully mature and dislocate the normal progenitor cells hence bringing the normal homeostatic processes out of balance. The fms-like tyrosine kinase 3 (Flt3) is expressed on multipotential HSC and progeni¬tor cells, suggesting a critical role in stem cell development and differentiation. In 1996 Nakao et al. were the first to report a novel mutation in the Flt3 gene in a small number of AML patients. These mutations were shown to be internal tandem duplications, mainly involving a tyrosine rich stretch at the end of exon 14 (formerly known as exon 11), coding for the juxtamembrane domain of the receptor. Since at that time little was known about the biological characteristics and clinical relevance of Flt3/ITD this led us to further characterise these mutations, the main aim of the experiments described in this thesis.

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