BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?

Sachiko Kawashima-Goto; Toshihiko Imamura; Chihiro Tomoyasu; Mio Yano; Hideki Yoshida; Atsushi Fujiki; Shinichi Tamura; Shinya Osone; Hiroyuki Ishida; Akira Morimoto; Hiroshi Kuroda; Hajime Hosoi

doi:10.1371/journal.pone.0132926

BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?

PLoS One. 2015 Jul 14;10(7):e0132926. doi: 10.1371/journal.pone.0132926. eCollection 2015.

Affiliations

¹ Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
² Department of Pediatrics, Matsushita Memorial Hospital, Moriguchi, Japan.
³ Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan.
⁴ Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan; Department of Pediatrics, Matsushita Memorial Hospital, Moriguchi, Japan.
⁵ Department of Pediatrics, Jichi Medical University School of Medicine, Shimotuke, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Biphenyl Compounds / pharmacology*
Cell Line, Tumor
Coculture Techniques
Gene Expression Regulation, Leukemic / drug effects
Gene Expression Regulation, Leukemic / genetics
Humans
Jurkat Cells
MEF2 Transcription Factors / genetics
Mice
Nitrophenols / pharmacology*
Piperazines / pharmacology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Prednisolone / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Sulfonamides / pharmacology*
fms-Like Tyrosine Kinase 3 / genetics

Substances

ABT-737
BCL2 protein, human
Biphenyl Compounds
MEF2 Transcription Factors
MEF2C protein, human
Nitrophenols
Piperazines
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
Prednisolone
FLT3 protein, human
fms-Like Tyrosine Kinase 3

Grants and funding

This work was supported by grants for Clinical Cancer Research and Research on Measures for Intractable Diseases from the Japanese Ministry of Health, Labor, and Welfare, by grants-in-aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and by grants for the Japan Foundation for Pediatric Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.