Abstract
Retroviral transduction of the BCR-ABL kinase into primary mouse bone marrow cells lacking the Arf tumor suppressor rapidly generates polyclonal populations of continuously self-renewing pre-B cells, virtually all of which have leukemic potential. Intravenous infusion of 20 such cells into healthy syngeneic mice induces rapidly fatal, transplantable lymphoblastic leukemias that resist imatinib therapy. Introduction of BCR-ABL into Arf-null severe combined immunodeficient (SCID) bone marrow progenitors lacking the cytokine receptor common gamma-chain yields leukemogenic pre-B cells that exhibit greater sensitivity to imatinib in vivo. Hence, salutary cytokines in the hematopoietic microenvironment can facilitate leukemic proliferation and confer resistance to targeted therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / therapeutic use
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Benzamides
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / physiology
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Cytokines / pharmacology*
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Fusion Proteins, bcr-abl / genetics*
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Hematopoietic Stem Cells / pathology
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Imatinib Mesylate
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Models, Biological
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Neoplasm Transplantation / pathology
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Piperazines / therapeutic use*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Pyrimidines / therapeutic use*
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Treatment Failure
Substances
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Antineoplastic Agents
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Benzamides
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Cytokines
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Piperazines
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Pyrimidines
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Imatinib Mesylate
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Fusion Proteins, bcr-abl