Abstract |
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.
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Authors | Richard T Williams, Martine F Roussel, Charles J Sherr |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 17
Pg. 6688-93
(Apr 25 2006)
ISSN: 0027-8424 [Print] United States |
PMID | 16618932
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzamides
- Cdkn2a protein, mouse
- Cyclin-Dependent Kinase Inhibitor p16
- Interleukin-7
- Piperazines
- Pyrimidines
- Tumor Suppressor Protein p14ARF
- Imatinib Mesylate
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Topics |
- Alleles
- Animals
- Antineoplastic Agents
(pharmacology)
- B-Lymphocytes
(drug effects, metabolism, pathology)
- Benzamides
- Bone Marrow Transplantation
- Cyclin-Dependent Kinase Inhibitor p16
- Genes, abl
- Hematopoietic Stem Cells
(drug effects, metabolism, pathology)
- Humans
- Imatinib Mesylate
- Interleukin-7
(pharmacology)
- Leukemia, Lymphoid
(drug therapy, genetics, pathology)
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, genetics, pathology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplasm Transplantation
- Piperazines
(pharmacology)
- Pyrimidines
(pharmacology)
- Tumor Cells, Cultured
- Tumor Suppressor Protein p14ARF
(deficiency, genetics)
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