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Bcl-xL and Akt cooperate to promote leukemogenesis in vivo

Oncogene volume 22, pages 688–698 (2003)Cite this article

Abstract

To analyse individual factors that may contribute to leukemic transformation in vivo, we have developed a murine model of leukemogenesis based on the early hematopoietic precursor cell FL5.12. FL5.12 cells are interleukin-3 (IL-3) dependent for growth, proliferation, and survival. Relative resistance to cell death following IL-3 withdrawal can be conferred by either overexpression of the Bcl-xL apoptotic inhibitor, or constitutive activation of the serine/threonine kinase Akt. The ability of Bcl-xL or a constitutively active myristylated Akt to promote leukemic transformation of FL5.12 cells was compared in athymic nu+/nu+ mice. Bcl-xL alone could not promote leukemic transformation, but mice injected with FL5.12 cells overexpressing Bcl-xL and a dominant-negative p53 construct developed leukocytosis and blastic infiltration of lymph nodes, spleen, and liver with features of a high-grade lymphoid malignancy. In contrast to the cells injected into these animals, cell lines derived from the mice were able to proliferate in the absence of IL-3, and were found to have constitutively activated Akt. This constitutive activation was associated with a variety of alterations of the signaling pathway regulating Akt activity, including alterations of PTEN mRNA and protein expression. In addition, some of these leukemic clones demonstrated concurrent constitutive upregulation of ERK activity. A constitutively active Akt construct introduced into FL5.12 cells promoted similar clonal expansion in vivo, with emergence of clonal IL-3-independent proliferation. Bcl-xL and Akt appeared to function cooperatively in this model, enhancing rapid clonal outgrowth in vivo relative to Akt alone. These results implicate activated Akt and growth-factor independence in leukemogenic transformation, and demonstrate the potential for in vivo analysis of genetic determinants of leukemogenesis.

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Acknowledgements

We thank Michelle Le Beau for several helpful discussions regarding this project and manuscript, and Theodore Karrison for statistical analysis. This work was supported by NIH CA81138 (CMR).

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Authors and Affiliations

  1. Department of Medicine, University of Chicago, Chicago, 60637, IL, USA

    Robyn Karnauskas, Qun Niu & Charles M Rudin

  2. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, PA, USA

    Sunit Talapatra & David R Plas

  3. Ben May Institute for Cancer Research, University of Chicago, Chicago, 60637, IL, USA

    Marianne E Greene & John D Crispino

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  1. Robyn Karnauskas
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  2. Qun Niu
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  3. Sunit Talapatra
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Correspondence to Charles M Rudin.

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Karnauskas, R., Niu, Q., Talapatra, S. et al. Bcl-xL and Akt cooperate to promote leukemogenesis in vivo. Oncogene 22, 688–698 (2003). https://doi.org/10.1038/sj.onc.1206159

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