Structural and functional alterations of FLT3 in acute myeloid leukemia.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research, Volume 15, Issue 13, p.4263-9 (2009)

Keywords:

2009, Clinical Research Division, fms-Like Tyrosine Kinase 3, Gene Duplication, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, Models, Biological, Mutation, Prognosis, Protein Structure, Tertiary, Structure-Activity Relationship

Abstract:

Hematopoiesis is highly regulated through cytokine-induced stimulation of multiple signal transduction pathways in order to mediate appropriate differentiation and proliferation of specific progenitor populations. Ligand-induced stimulation of the FMS-like tyrosine kinase 3 (FLT3) leads to activation of multiple downstream effector pathways resulting in differentiation and proliferation of specific progenitor cell populations. Genomic alterations of the FLT3 gene, including FLT3 internal tandem duplication (FLT3/ITD) and FLT3 activation loop mutation (FLT3/ALM) lead to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways, contribute to myeloid pathogenesis, and have been linked to response to therapy and clinical outcome. Exploring the mechanisms by which these FLT3 alterations lead to dysregulated proliferation should provide a better understanding of the molecular pathogenesis of acute myeloid leukemia (AML) and may provide insights into potential therapeutic interventions. FLT3 inhibitors are under evaluation for their efficacy in AML patients with FLT3 mutations.