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Signal Transduction

Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support

Abstract

Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-B-ALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV+/PI+ apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).

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Acknowledgements

We thank Dr Tucker LeBien and Nisha Shah (University of Minnesota Cancer Center) for the BLIN-2 cell line. FEB was supported in part by Institutional Grant ECU-5-89812 from the American Cancer Society. JAM was supported in part by grants RO1 CA51025 and RO1 CA 098195 from the US Public Health Service, National Institutes of Health.

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Correspondence to F E Bertrand.

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Bertrand, F., Spengemen, J., Shelton, J. et al. Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 19, 98–102 (2005). https://doi.org/10.1038/sj.leu.2403560

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  • DOI: https://doi.org/10.1038/sj.leu.2403560

Keywords

  • B-ALL
  • mTOR
  • microenvironment
  • MEK
  • EGF-R

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