title: BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?
abstract: Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as a high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL). Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored. Analysis of the gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than typical T-ALL. Using human T-ALL and BaF3 cell lines with high expression levels of MEF2C, the present study tested whether the BCL2 inhibitor (ABT-737) restores the sensitivity to prednisolone (PSL), because MEF2C causes PSL resistance, possibly by augmenting the anti-apoptotic activity of BCL2. Treatment with PSL and ABT-737 caused a significant reduction in the IC50 of PSL in the MEF2C-expressing LOUCY cells, in addition to the MEF2C-transduced BaF3 cells, but not in the non-MEF2C-expressing Jurkat cells. The combination treatment significantly accelerated the killing of primary leukemic blast cells of ETP-ALL with high expression levels of MEF2C, which were co-cultured with murine stromal cells. These findings suggest that BCL2 inhibitors may be a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kawashima-Goto
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tomoyasu
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, Matsushita Memorial Hospital, Moriguchi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujiki
authors.affiliation: Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Osone
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan; Department of Pediatrics, Matsushita Memorial Hospital, Moriguchi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Pediatrics, Jichi Medical University School of Medicine, Shimotuke, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011239:Prednisolone / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C501332:ABT-737; C000595707:BCL2 protein, human; D001713:Biphenyl Compounds; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D011239:Prednisolone; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3