Clinical implications of c-Kit mutations in acute myelogenous leukemia

Abstract

c-Kit is a receptor tyrosine kinase (RTK) with a pivotal role in melanogenesis, gametogenesis, and hematopoiesis. Aberrantly activated RTK and related downstream signaling partners were identified as key elements in the molecular pathogenesis of several malignancies. This finding culminated in a two-class model integrating constitutive activating and maturation arrest-inducing mutations as key elements for the pathogenesis of acute myelogenous leukemia (AML). c-Kit is expressed by myeloblasts in about 60% to 80% of patients, and the most frequently observed activating RTK mutations in AML (next to FLT3) are mutations or internal tandem duplications in c-Kit, with an overall incidence of 17%. The identification of small-molecule tyrosine kinase inhibitors capable of blocking key kinase switches introduced a paradigm change in the treatment of diseases like gastrointestinal stromal tumors and chronic myelogenous leukemia. Despite encouraging preclinical data, it appears that a complex clonal disease like AML will probably benefit from a synergistic approach of targeted drugs used (at least for now) in combination with conventional chemotherapy.

Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target

“…We reported that Axl is necessary for maintaining activation of c-Kit, 20 which belongs to the same type III RTK family as FLT3. 31 Indeed, FLT3 inhibitors used in clinical trials have also been shown to inhibit c-Kit activity. 18 We thus hypothesized that FLT3 could be a potential target of Axl, at least in cases of FLT3- with Axl-Fc, the physical interaction between Axl and FLT3 was disrupted ( Figure 3C), suggesting not only that Axl is a positive regulator of FLT3 phosphorylation but also that this regulation likely occurs through physical interaction between activated Axl and FLT3.…”

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

“…25 Implication of the D816V mutation in the pathogenesis of myeloproliferative disease demonstrates a critical role of KIT D816V transduced signals in the development of myeloid cells. 26,27 Although extrapolations regarding the physiological mechanisms of Kit signaling during myeloid cell differentiation must be made with caution, it is thus reasonable that similar signaling events are activated by the mutant KIT D816V receptor and valuable insights can be provided by such a model. We therefore generated a conditional mouse line with knock-in of a chimeric KIT receptor carrying the D816V mutation in the ROSA26 locus.…”

Activating Mutations and Targeted Therapy in Cancer

“…Other kinase activating mutations have been found in the oncogene c-KIT in gastrointestinal stromal tumors (GIST), acral or mucosal melanoma, endometrial carcinoma, germ cell tumors, myeloproliferative diseases, and leukemias, which is the mutations cause constitutive activation of c-KIT (Malaise, Steinbach et al 2009). c-KIT is a transmembrane cytokine receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells.…”