Abstract 3130: The short form of the receptor tyrosine kinase Ron is expressed in acute myeloid leukemia, regulated by methylation and sensitizes leukemic cells to c-Met inhibitors
Authors: Fialin Camille , Vergez François , Bertoli Sarah , Mas Véronique Mansat-De , Demur Cécile , Delabesse Eric , Payrastre Bernard , Manenti Stéphane , Roche Serge , Récher Christian 
Published: June 2012

Acute myeloid leukemia (AML) are heterogeneous hematopoietic disorders characterized by an accumulation of immature leukemic cells and by a block in cell differentiation. In spite of recent therapeutical advances and frequent complete remission, all patients shortly relapse leading to an urgent need for more specific targeted treatments. Beside the development of epigenetic and differentiation therapies for AML, therapeutic strategies targeting protein tyrosine kinases are also attractive and promising. Here we report a novel oncogenic activity of the cMet related receptor tyrosine kinase Ron (Recepteur d'Origine Nantais) in AML. Ron is expressed in most epithelial tissues as well as in normal hematopoietic CD34+ cells and macrophages. Its oncogenic properties have been documented in solid tumors and a truncated form of Ron (short form of Ron, sf-Ron) lacking most of the Ron receptor extracellular domain but retaining the whole transmembrane and intracellular domains has been detected in several tissues and in KG1 AML cell line. We found that sf-Ron was expressed in 44% of AML patients cells (n=87), whereas 38% of patient cells did not express neither fl-Ron nor sf-Ron. Interestingly only fl-Ron is expressed in CD34+ normal cells suggesting that sf-Ron could be specific of leukemic cells. Accordingly, sf-Ron was found to be active in AML samples unlike the fl-Ron. Inhibition of sf-Ron activity by either the dual c-Met/Ron inhibitor SU-11274 or a specific siRNA approach inhibited clonogenic properties and induced apoptosis only in sf-RON positive AML cells. Moreover, the leukemic compartment CD34+CD38-CD123+ often associated with the chemoresistance and clinical relapse, was also sensitive to this treatment. Additionally, we observed an original link between sfRon and the tyrosine kinase Lyn previously described to be strongly deregulated in AML cells. Indeed, we showed that sf-Ron is associated with Lyn and these two tyrosine kinases activate each other. Finally, a recent study described an epigenetic mechanism of expression regulation of Ron and sf-Ron, showing the existence of two distinct CpG islands. Indeed, 5-Azacytidine treatment of AML cells led to a marked down-regulation of sf-Ron in AML cells. This effect was accompanied by a strong reduction of Lyn activity. In conclusion, our study suggests that targeting sf-Ron activity might be of therapeutic value in AML and uncovers novel mechanisms by which hypomethylating agents would act on AML and myelodysplastic syndromes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3130. doi:10.1158/1538-7445.AM2011-3130