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.
Williams
Richard T
RT
Department of Oncology, St. Jude Children's Research Hospital, USA. richard.williams@stjude.org
Sherr
Charles J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D000068877:Imatinib Mesylate; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D001549:Benzamides; D015851:Interleukin-7; D010879:Piperazines; D011743:Pyrimidines; D025803:Tumor Suppressor Protein p14ARF; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl