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

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.