title: Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression.
abstract: OBJECTIVE
  The prognosis for diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2 remains dismal; there is an urgent need to clarify the significance of these two oncogenes as therapeutic targets for a more effective treatment strategy.
  
  
  METHODS
  We established two novel cell lines, KPUM-MS3 and KPUM-UH1, from two chemoresistant patients with diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2, and investigated the significance of c-Myc and Bcl-2 as therapeutic targets.
  
  
  RESULTS
  KPUM-MS3 possesses t(14;18)(q32;q21) chromosomal translocation and KPUM-UH1 bcl-2 gene amplification, both of which account for Bcl-2 overexpression. Chromosomal translocation t(8;14)(q24;q34) was found to coexist only in KPUM-UH1, overexpression of pvt-1 messenger RNA was detected only in KPUM-MS3, and reduced expression of miR-143 and miR-145 was identified in both. Working together, these abnormalities can contribute to c-Myc overexpression. Using ABT-263, an inhibitor for Bcl-2, and 10058-F4, an inhibitor for c-Myc, we found that both cell lines were more highly sensitive to cell death as a result of Bcl-2 inhibition than of c-Myc inhibition. When combined with genotoxic agents, ABT-263 exerted additive and/or synergistic cell-killing effects, while 10058-F4 showed, at most, a modest combinatory effect. Importantly, the combination of ABT-263 and 10058-F4 had a synergistic cell-killing effect on both cell lines.
  
  
  CONCLUSIONS
  Our data suggest that Bcl-2 is a better therapeutic target than c-Myc, but attacking both Bcl-2 and c-Myc would be an even more effective treatment strategy for diffuse large B-cell lymphomas with concurrent Bcl-2 and c-Myc overexpression.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Sasaki
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Hisao
authors.initials: H
authors.lastname: Nagoshi
authors.forename: Mio
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimura
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishida
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horiike
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032681:Spectral Karyotyping; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014178:Translocation, Genetic
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D013449:Sulfonamides; D013844:Thiazoles; D003561:Cytarabine; D005047:Etoposide; D004317:Doxorubicin; C528561:navitoclax