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

Leukemia. 2013 Feb;27(2):325-35. doi: 10.1038/leu.2012.240. Epub 2012 Aug 20.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Azacitidine / pharmacology
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Flow Cytometry
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Immunoprecipitation
  • Indoles / pharmacology
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • 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
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • 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
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Young Adult
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
  • Antimetabolites, Antineoplastic
  • BAD protein, human
  • Indoles
  • Multiprotein Complexes
  • Piperazines
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Small Interfering
  • Sulfonamides
  • bcl-Associated Death Protein
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Azacitidine