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Adv Exp Med Biol. 2003;532:121-40.

Mutated tyrosine kinases as therapeutic targets in myeloid leukemias.

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  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Abstract

Tyrosine kinases are commonly mutated and activated in both acute and chronic myeloid leukemias. Here, we review the functions, signaling activities, mechanism of transformation, and therapeutic targeting of two prototypic tyrosine kinase oncogenes, BCR-ABL and FLT3, associated with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), respectively. BCR-ABL is generated by the Philadelphia chromosome translocation between chromosomes 9 and 22, creating a chimeric oncogene in which the BCR and c-ABL genes are fused. The product of this oncogene, BCR-ABL, has elevated ABL tyrosine kinase activity and transforms hematopoietic cells by exerting a wide variety of biological effects, including reduction in growth factor dependence, enhanced viability, and altered adhesion of chronic myelocytic leukemia (CML) cells. Elevated tyrosine kinase activity of BCR-ABL is critical for activating downstream signalling cascades and for all aspects of transformation, explaining the remarkable clinical efficacy of the tyrosine kinase inhibitor, imatinib mesylate (STI571). By comparison, FLT3 is mutated in about one third of all cases of AML, most often through a mechanism that involves an internal tandem duplication (ITD) of a small number of amino acid residues in the juxtamembrane domain of the receptor. As is the case for BCR-ABL, these mutations activate the kinase activity constitutively, activate multiple signaling pathways, and result in an augmentation of proliferation and viability. Transformation by FLT3-ITD can readily be observed in murine models, and FLT3 cooperates with other types of oncogenes to create a fully transformed acute leukemia. FLT3 tyrosine kinase inhibitors are currently being evaluated in clinical trials and may be very useful therapeutic agents in AML.

PMID:
12908554
[PubMed - indexed for MEDLINE]
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