Abstract
Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFβR (H/P) and AML1/ETO from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within 1 week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (lineage(-)Sca-1(+)c-Kit(+) immunophenotype) normalized. Supplementation of imatinib with granulocyte colony-stimulating factor or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse.
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 / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Arsenic Trioxide
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Arsenicals / administration & dosage
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Benzamides / administration & dosage
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Benzamides / pharmacology*
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Blotting, Western
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Bone Marrow Transplantation
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Granulocyte Colony-Stimulating Factor / administration & dosage
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Imatinib Mesylate
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Mice, Inbred C57BL
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Mice, Transgenic
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Myeloproliferative Disorders / drug therapy*
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / metabolism
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Neoplasm Recurrence, Local
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Oligonucleotide Array Sequence Analysis
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Oxides / administration & dosage
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Piperazines / administration & dosage
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Piperazines / pharmacology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology*
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Reverse Transcriptase Polymerase Chain Reaction
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Treatment Outcome
Substances
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Antineoplastic Agents
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Arsenicals
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Benzamides
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Hip1 protein, mouse
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Oxides
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Piperazines
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Pyrimidines
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Runx1 protein, mouse
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Granulocyte Colony-Stimulating Factor
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Imatinib Mesylate
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Arsenic Trioxide