The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors

• Published in: Leukemia Vol. 27; no. 2; pp. 325 - 335
• Main Authors: Fialin, C, Larrue, C, Vergez, F, Sarry, J E, Bertoli, S, Mansat-De Mas, V, Demur, C, Delabesse, E, Payrastre, B, Manenti, S, Roche, S, Récher, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2013; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/154/436/1729; 631/67/68; 692/699/67/1990/283/1897; Acute myeloid leukemia; Adolescent; Adult; Aged; Aged, 80 and over; AKT protein; Antibodies; Anticancer properties; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; Azacitidine - pharmacology; Azacytidine; bcl-Associated Death Protein - genetics; bcl-Associated Death Protein - metabolism; Blotting, Western; Cancer Research; CD34 antigen; Cell growth; Cell lines; Cell Proliferation - drug effects; Cells, Cultured; Cellular signal transduction; Clinical trials; Critical Care Medicine; Drug Resistance, Neoplasm - drug effects; Female; Flow Cytometry; Gene mutations; Growth factors; Hematology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Immunoprecipitation; Indoles - pharmacology; Inhibitors; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Medicine; Medicine & Public Health; Middle Aged; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Oncology; original-article; Pathogenesis; Patients; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Phosphotransferases; Physiological aspects; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Ron protein; Signal transduction; Signal Transduction - drug effects; Signaling; src-Family Kinases - genetics; src-Family Kinases - metabolism; Sulfonamides - pharmacology; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tyrosine; Young Adult; France; United States > US; RON; Lyn; 5-azacytidine; MET inhibitors; MST1R
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.240

Several receptor tyrosine kinases (TKs) are involved in the pathogenesis of acute myeloid leukemia (AML). Here, we have assessed the expression of the Recepteur d’Origine Nantais (RON) in leukemic cell lines and samples from AML patients. In a series of 86 AML patients, we show that both the full length and/or the short form (sf) of RON are expressed in 51% and 43% of cases, respectively. Interestingly, sfRON is not expressed in normal CD34+ hematopoietic cells and induces part of its oncogenic signaling through interaction with the Src kinase Lyn. sfRON-mediated signaling in leukemic cells also involves mTORC1, the proapoptotic bcl2-family member, BAD, but not the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, the expression of sfRON was specifically downregulated by 5-azacytidine (AZA). Conversely, AZA could induce the expression of sfRON in sfRON-negative leukemic cells suggesting that the activity of this drug in AML and myelodysplastic syndromes could involve modulation of TKs. cMET/RON inhibitors exhibited an antileukemic activity exclusively in AML samples and cell lines expressing sfRON. These results might support clinical trials evaluating cMET/RON inhibitors in AML patients expressing sfRON.