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Role of p21WAF1/CIP1 as an attenuator of both proliferative and drug-induced apoptotic signals in BCR-ABL-transformed hematopoietic cells

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Abstract

The constitutive tyrosine kinase activity of the BCR-ABL fusion protein plays a crucial role in the pathogenesis of chronic myeloid leukemia and promotes growth factor-independent survival of hematopoietic cells. In 32D cells, expression levels of retrovirally transduced BCR-ABL were positively correlated with the levels of the cell cycle regulator protein p21, and this upregulation of p21 expression depended on the kinase activity of BCR-ABL. To assess the role of p21 on BCR-ABL-positive hematopoietic cells, we compared proliferation and drug-induced apoptosis in bone marrow (BM) cells from wild-type and p21 knockout mice after retroviral transfer of the BCR-ABL fusion gene. As compared with wild-type cells, p21 knockout cells showed increased proliferation, suggesting that p21 acted as an attenuator of BCR-ABL-mediated cell proliferation. In marked contrast, deletion of p21 promoted apoptosis induction by imatinib and taxol in BCR-ABL-transformed BM cells. These findings demonstrate that p21 has a dual function in BCR-ABL-transformed murine BM cells: It attenuates the effects of two apparently opposed phenomena such as BCR-ABL-mediated cell proliferation and drug-induced apoptosis. This dual function of p21 calls for a cautious evaluation of the suitability of p21 as a secondary target in anticancer therapy.

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Acknowledgments

This work was supported by grants Ha 1680/7-1 and 7-2 from the Deutsche Forschungsgemeinschaft. We thank D. Bund and C. Mayr for advice on FACS analysis, E. Buchdunger (Novartis Basel, Switzerland) for providing IM, and U. Just and T. Schroeder for kindly providing 32D cell lines.

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Author notes

  1. Karin Forster & Markus Warmuth

    Present address: GNF—Novartis Genomics Institute, 10657 John Jay Hopkins Drive, San Diego, CA, 92121, USA

  2. Olga Mitina

    Present address: MorphoSys AG, Lena-Christ-Str. 48, 82152, Planegg, Germany

Authors and Affiliations

  1. Clinical Cooperation Group Gene Therapy, GSF—Research Center for Environment and Health, Marchioninistrasse 25, 81377, Munich, Germany

    Karin Forster, Olga Mitina, Nicola Simon, Markus Warmuth, Günter Krause & Michael Hallek

  2. Sireen AG, Am Klopferspitz 19A, 82152, Munich, Germany

    Axel Obermeier

  3. Clinic I for Internal Medicine, University Hospital Cologne, Kerpener Str. 62, 50924, Cologne, Germany

    Günter Krause & Michael Hallek

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  1. Karin Forster
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Correspondence to Günter Krause.

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Forster, K., Obermeier, A., Mitina, O. et al. Role of p21WAF1/CIP1 as an attenuator of both proliferative and drug-induced apoptotic signals in BCR-ABL-transformed hematopoietic cells. Ann Hematol 87, 183–193 (2008). https://doi.org/10.1007/s00277-007-0400-9

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