Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia.
Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210(Bcr-Abl) and p185(Bcr-Abl)) induce B cell lympholeukemias when transplanted into lethally irradiated mice. If the activity of the Arf tumor suppressor is compromised, these donor cells initiate a much more highly aggressive and rapidly fatal disease. When mouse bone marrow cells expressing Bcr-Abl are placed in short-term cultures selectively designed to support the outgrowth of pre-B cells, only those lacking one or two Arf alleles can initiate lympholeukemias when inoculated into immunocompetent, syngeneic recipient mice. Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF (CDKN2A) tumor suppressor locus. Mice receiving Arf-/- or Arf+/- p210(Bcr-Abl)-positive pre-B cells do not achieve remission when maintained on high doses of oral imatinib therapy and rapidly succumb to lympholeukemia. Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib. Treatment of Arf-/-, p210(Bcr-Abl)-positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance, suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia.
Williams
Richard T
RT
Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Roussel
Martine F
MF
Sherr
Charles J
CJ
D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001549:Benzamides; D016026:Bone Marrow Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016313:Genes, abl; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D015851:Interleukin-7 / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency* / Q000235:genetics*
D000970:Antineoplastic Agents; D001549:Benzamides; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015851:Interleukin-7; D010879:Piperazines; D011743:Pyrimidines; D025803:Tumor Suppressor Protein p14ARF; D000068877:Imatinib Mesylate