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

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

doi:10.1371/journal.pone.0132926

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.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia, accounting for 10– 15% of childhood ALL cases
We found no significant differences in the expression levels of NOTCH1, LYL1, IL7R and LMO2 between the Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) and typical T-ALL cells (Table 1). q-PCR analysis demonstrated that MEF2C and FLT3 were expressed at significantly higher levels in early T-cell precursors (ETPs)-ALL than in typical T-ALL cells (MEF2C: p = 0.039, FLT3: p = 0.014) (Table 1, Fig 1)
Homminga et al first revealed that the expression level of MEF2C was high in immature T-ALL cases, as defined by gene expression profiling [13]

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia, accounting for 10– 15% of childhood ALL cases. With a wide use of intensive chemotherapy, the prognosis of childhood T-ALL has improved; nearly 80% of patients can currently be cured [1,2,3]. Approximately one-fifth of children with T-ALL succumb to the disease. To improve the PLOS ONE | DOI:10.1371/journal.pone.0132926. T-Cell Precursor-Acute Lymphoblastic Leukemia study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion