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The biology of chronic myelogenous leukemia:mouse models and cell adhesion

Oncogene volume 21, pages 8612–8628 (2002)Cite this article

Abstract

Chronic myelogenous leukemia (CML) is a biphasic neoplasm of the bone marrow that is precipitated by the Philadelphia chromosome, a t(9;22) balanced translocation that encodes a constitutively activated nonreceptor tyrosine kinase termed P210BCR-ABL. This oncoprotein has several intracellular functions; however, the most important effect of P210BCR-ABL leading to cell transformation is phosphorylation of signaling molecules through a constitutively active tyrosine kinase domain. Despite extensive knowledge of the structure and functional domains of BCR-ABL, its precise function in transformation is not known. Progress has been hampered, in part, by the lack of relevant CML models, as cell culture and in vitro assays do not mimic the pathogenesis of CML. Recently, there has been significant progress toward improving murine models that closely resemble human CML. This has allowed researchers to evaluate critical functions of BCR-ABL and has provided a model to test the efficacy of therapeutic medications that block these pathways. Our laboratory has developed two intersecting research programs to better understand the functioning of P210BCR-ABL in leukemogenesis. In one approach, we have developed a murine CML model by transferring HSCs that express BCR-ABL from a retroviral vector. All recipients develop a rapidly fatal MPD that shares several important features with CML. This model has been extremely useful for studying the function of BCR-ABL in the pathogenesis of CML. A second approach utilizes a quantitative cell detachment apparatus capable of measuring small changes in cell adhesion to investigate the mechanism by which P210BCR-ABL causes abnormal cell binding. Altered cell adhesion may contribute to the imbalance between proliferation and self-renewal in the hematopoietic progenitor compartment. To better understand the role abnormal adhesion may play in the development of leukemia, we have attempted to correlate the effects of functional P210BCR-ABL mutants in regulating adhesion and oncogenicity.

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Acknowledgements

We thank the members of the University of Pennsylvania John Morgan (IHGT) mouse and flow cytometry facilities. The flow cytometry studies were performed in the University of Pennsylvania Cancer Center Flow Cytometry and Cell Sorting Shared Resource (supported in part by the Lucille B Markey Trust and the NIH). Tissue processing was performed by the Gastroenterology Cell Morphology Core at the University of Pennsylvania (supported by NIH Center grant P30-DK50306). These studies were supported by NIH CA77570 and a Scholar Award from the Leukemia and Lymphoma Society to WS Pear. JA Wertheim acknowledges support from the Whitaker Foundation and the Medical Scientist Training Program.

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Authors and Affiliations

  1. Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jason A Wertheim, Lanwei Xu, Yiping He & Warren S Pear

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

    Jason A Wertheim, Juli P Miller, Lanwei Xu, Yiping He & Warren S Pear

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jason A Wertheim, Juli P Miller, Lanwei Xu, Yiping He & Warren S Pear

  4. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jason A Wertheim

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Wertheim, J., Miller, J., Xu, L. et al. The biology of chronic myelogenous leukemia:mouse models and cell adhesion. Oncogene 21, 8612–8628 (2002). https://doi.org/10.1038/sj.onc.1206089

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