The ARF tumor suppressor in acute leukemias: insights from mouse models of Bcr-Abl-induced acute lymphoblastic leukemia

Adv Exp Med Biol. 2007;604:107-14. doi: 10.1007/978-0-387-69116-9_9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Benzamides
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor*
  • Humans
  • Imatinib Mesylate
  • Interleukin-7 / metabolism
  • Mice
  • Piperazines / pharmacology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Pyrimidines / pharmacology
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p14ARF / physiology*

Substances

  • Antineoplastic Agents
  • Benzamides
  • Interleukin-7
  • Piperazines
  • Pyrimidines
  • Tumor Suppressor Protein p14ARF
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl