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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8612-8628
Number of pages17
JournalOncogene
Volume21
Issue number56 REV. ISS. 7
DOIs
StatePublished - Dec 9 2002

Keywords

  • BCR-ABL
  • CML
  • Cell adhesion
  • Mouse model
  • Philadelphia chromosome

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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