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.

MEF2 signaling and human diseases

“…In leukemic patients, the ectopic expression of MEF2s caused by chromosomal rearrangements is responsible for the development of leukemia. A high level expression of MEF2C is observed in T-cell acute lymphoblastic leukemia (T-ALL) [ 42 , 43 ]. The chromosomal translocation generates reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1 fusion genes that promotes oncogenic properties in NIH 3T3 cells [ 44 ].…”

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

“…Although there were too few patients in the present series to draw any definitive conclusions, I-5q marks a particularly high-risk subgroup of immature/ETP ALL for which alternative targeted therapies should be developed. Among them, JAK/STAT inhibitors, which are highly effective in ETP-ALL xenograft models, 43 and the BCL2 inhibitor ABT-737, which restores the sensitivity to steroids in cell lines with high MEF2C expression, 44,45 might be considered in the treatment of these refractory leukemias.…”

Clinical and molecular characterization of early T-cell precursor acute lymphoblastic leukemia

“…Lu et al [13] tested the role of DNA methyltransferase inhibitor decitabine in pretreating ETP-ALL through the vitro test and suggesting that decitabine could enhance the chemosensitivity in ETP-ALL. [14] Sachiko Kawashima-Goto [15] suggested the Bcl2 inhibitor (ABT-737) can recover the sensitivity to prednisolone in leukemic cells with a high expression of MEF2C. Based on this, inhibition of Bcl2 might become a therapeutic candidate for ETP-ALL patients.…”

“…They proposed the combination of CDKN1B deletions with the expression of MEF2C considered as a driving oncogene in ETP-ALL. And Kawashima-Goto et al [15] suggested BCL2 inhibitor (ABT-737) may be a restorer of prednisolone sensitivity in ETP-ALL with high MEF2C expression. Lmo2 is an oncogenic transcription factor that is frequently over-expressed in T-ALL including ETP-ALL which must combine with its partner SCL or LYL1 to drive leukemia.…”