Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia

Abstract

Durable responses to imatinib monotherapy are rarely seen in aggressive forms of Philadelphia chromosome positive (Ph+) leukemias. To investigate the possible cause of treatment failure we examined the role of protein kinase C epsilon (PKCE), an oncogene highly implicated in the development of solid tumors and resistance to chemotherapy. We found high levels of PKCE transcripts in Ph+ acute lymphoblastic leukemia (ALL) cells from patients and cell lines, and imatinib resistant chronic myeloid leukemia, which were also less responsive to imatinib-induced apoptosis than Ph+ cells with lower PKCE expression. Furthermore, the siRNA-mediated knockdown or peptide inhibition of PKCE in Ph+ cells increased imatinib-induced apoptosis while overexpression of PKCE reduced imatinib-induced apoptosis, with concomitant increase in the pro-survival factor AKT. Our results suggest PKCE plays a protective role against apoptosis induced by BCR-ABL inhibition in Ph+ leukemias with high PKCE expression, such as Ph+ ALL.

Keywords::

• BCR-ABL
• imatinib resistance
• PKC epsilon

Acknowledgements

We wish to thank Dr Carsten Schmitt-Pieffer for the PKCE constructs and for his advice relating to the PKCE peptide inhibitory experiments. This study was supported in part by grants from the Arrow Bone Marrow Transplant Foundation, St Vincent's Clinic Foundation, the Hematology Research Fund of St Vincent's Hospital, Australian Postgraduate Award (THL) and the UK NIHR Biomedical Research Centre funding scheme (JVM).

Potential conflict of interest

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Supplementary material available online

Supplementary Tables I and II listing genes identified by microarray analysis to be up- or down regulated in leukemic cells from Ph+ ALL patients treated with imatinib in vivo.