title: Sensitivity of acute myeloid leukemia Kasumi-1 cells to binase toxic action depends on the expression of KIT and АML1-ETO oncogenes.
abstract: Some RNases selectively attack malignant cells, triggering an apoptotic response, and therefore are considered as alternative chemotherapeutic drugs. Here we studied the effects of Bacillus intermedius RNase (binase) on murine myeloid progenitor cells FDC-P1; transduced FDC-P1 cells ectopically expressing mutated human KIT N822K oncogene and/or human AML1-ETO oncogene; and human leukemia Kasumi-1 cells expressing both of these oncogenes. Expression of both KIT and AML1-ETO oncogenes makes FDC-P1 cells sensitive to the toxic effects of binase. Kasumi-1 cells were the most responsive to the toxic actions of binase among the cell lines used in this work with an IC50 value of 0.56 µM. Either blocking the functional activity of the KIT protein with imatinib or knocking-down oncogene expression using lentiviral vectors producing shRNA against AML1-ETO or KIT eliminated the sensitivity of Kasumi-1 cells to binase toxic action and promoted their survival, even in the absence of KIT-dependent proliferation and antiapoptotic pathways. Here we provide evidence that the cooperative effect of the expression of mutated KIT and AML1-ETO oncogenes is crucial for selective toxic action of binase on malignant cells. These findings can facilitate clinical applications of binase providing a useful screen based on the presence of the corresponding target oncogenes in malignant cells.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Mitkevich
authors.forename: Irina Y
authors.initials: IY
authors.lastname: Petrushanko
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Spirin
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Fedorova
authors.forename: Olga V
authors.initials: OV
authors.lastname: Kretova
authors.forename: Nickolai A
authors.initials: NA
authors.lastname: Tchurikov
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Prassolov
authors.forename: Olga N
authors.initials: ON
authors.lastname: Ilinskaya
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Makarov
mesh_terms: D000818:Animals; D017209:Apoptosis; D001407:Bacillus / Q000201:enzymology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004722:Endoribonucleases / Q000633:toxicity*; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D013997:Time Factors
chemical_list: C107844:AML1-ETO fusion protein, human; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D004722:Endoribonucleases; C022543:ribonuclease T(2)