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Bcl2 phosphorylation and active PKC α are associated with poor survival in AML

Leukemia volume 20, pages 1316–1319 (2006)Cite this article

Bcl2 was identified as the cellular oncogene product associated with the t(14,18) translocation commonly seen in B-cell lymphomas and is the founding member of a family of proteins that regulate apoptosis.1 Bcl2 protects cells from a wide range of stress challenges and thus high Bcl2 levels would be predicted to favor chemoresistance.1, 2 However, Bcl2 expression levels alone do not always correlate with poor prognosis (e.g. some acute myeloid leukemias (AML) patient subsets, pediatric acute lymphoblastic leukemia patients).2 As Bcl2 expression alone cannot explain its full and potent antiapoptotic activity, other regulatory mechanisms must be involved.

The phosphorylation status of Bcl2 influences its function.3, 4, 5, 6 Growth agonist-induced phosphorylation of Bcl2 at serine 70 is required for Bcl2's full and potent antiapoptotic function.4, 5, 6 PKC α and extracellular signal-related kinase (ERK) have been identified as Bcl2 kinases that promote survival.5, 6 In hematopoietic cell lines, overexpression of exogenous kinase or treatment of cells with kinase agonist (i.e. bryostatin for PKC α and aurintricarboxylic acid for ERK) results in enhanced Bcl2 phosphorylation and increased resistance to apoptosis on induction of stress challenges (i.e. IL-3 withdrawal or treatment of cells with chemotherapeutic agents).5, 6, 7 Consequently, the phosphorylation status of Bcl2 in AML blast cells or any other human malignancy is unknown. Furthermore, the consequence of phosphorylated Bcl2 on the survival of AML blast cells has yet to be determined. In the present study, we investigate Bcl2 phosphorylation status using metabolic radiolabeling and activation status of PKC α and ERK in blast cells from AML patients and examine their effect on patient survival. We find that Bcl2 is phosphorylated in nearly half the AML blast cells tested. Furthermore, Bcl2 is always phosphorylated in AML blast cells with activated PKC α and ERK but never in cells that lack both activated kinases. Finally, AML patients with blast cells expressing phosphorylated Bcl2 exhibit shorter overall survival (particularly when PKC α was active) compared to patients with blast cells expressing unphosphorylated Bcl2. This finding is consistent with our previous study that determined that expression levels of proteins (i.e. Bax and PKC α) that affect the functional status of Bcl2 modify the prognostic impact of Bcl2.8

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Authors and Affiliations

  1. Division of Cell Signaling, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA

    S Kurinna & P P Ruvolo

  2. Department of Blood and Marrow Transplantation, MD Anderson Cancer Center, Houston, TX, USA

    M Konopleva, W Chen, S Kornblau, R Contractor, M Andreeff & P P Ruvolo

  3. Department of Biostatistics and Applied Mathematics, MD Anderson Cancer Center, Houston, TX, USA

    S L Palla

  4. Shands Cancer Center, University of Florida, Gainesville, FL, USA

    X Deng & W S May

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  1. S Kurinna
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  2. M Konopleva
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  10. P P Ruvolo
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Kurinna, S., Konopleva, M., Palla, S. et al. Bcl2 phosphorylation and active PKC α are associated with poor survival in AML. Leukemia 20, 1316–1319 (2006). https://doi.org/10.1038/sj.leu.2404248

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