The Arf Tumor Suppressor in Acute Leukemias: Insights from Mouse Models of Bcr–Abl-Induced Acute Lymphoblastic Leukemia

  • Richard T. Williams
  • Charles J. Sherr
Part of the Advances In Experimental Medicine And Biology book series (AEMB, volume 604)

The prototypical Bcr–Abl chimeric oncoprotein is central to the pathogenesis of chronic myelogenous leukemias (CMLs) and a subset of acute lymphoblastic leukemias (Ph+ ALLs). The constitutive tyrosine kinase transforms either hematopoietic stem cells (in CML) or committed pre-B lymphoid progenitors (in Ph+ ALL) to generate these distinct diseases. The INK4A/ARF tumor suppressor locus is frequently deleted in both B- and T-lineage ALLs, including Ph+ ALL, whereas the locus remains intact in CML. In murine bone marrow transplant models and after transfer of syngeneic Bcr–Abl-transformed pre-B cells into immunocompetent recipient animals, Arf gene inactivation dramatically decreases the latency and enhances the aggressiveness of Bcr–Abl-induced lymphoblastic leukemia. Targeted inhibition of the Bcr–Abl kinase with imatinib provides highly effective therapy for CML, but Ph+ ALL patients do not experience durable remissions. Despite exquisite in vitro sensitivity of Arf-null, BCR–ABL+ pre-B cells to imatinib, these cells efficiently establish lethal leukemias when introduced into immunocompetent mice that receive continuous, maximal imatinib therapy. Bcr–Abl confers interleukin-7 (IL-7) independence to pre-B cells, but imatinib treatment restores the requirement for this cytokine. Hence, IL-7 can reduce the sensitivity of Bcr–Abl+ pre-B cells to imatinib. Selective inhibitors of both Bcr–Abl and the IL-7 transducing JAK kinases may therefore prove beneficial in treating Ph+ ALL.


Chronic Myelogenous Leukemia Imatinib Resistance Breakpoint Cluster Region Kinase Domain Mutation Tyrosine Kinase Inhibitor Imatinib 
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Copyright information

© Springer 2007

Authors and Affiliations

  • Richard T. Williams
    • 1
  • Charles J. Sherr
    • 2
  1. 1.Department of OncologySt. Jude Children's Research HospitalUSA
  2. 2.Department of Genetics and Tumor Cell Biology St. Jude Children's ResearchHoward Hughes Medical InstituteUSA

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