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Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells
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....
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025985/ https://www.ncbi.nlm.nih.gov/pubmed/24240679 http://dx.doi.org/10.1038/onc.2013.484 |
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author | Philips, Steven T. Hildenbrand, Zacariah L. Oravecz-Wilson, Katherine I. Foley, S. Blake Mgbemena, Victoria E. Ross, Theodora S. |
author_facet | Philips, Steven T. Hildenbrand, Zacariah L. Oravecz-Wilson, Katherine I. Foley, S. Blake Mgbemena, Victoria E. Ross, Theodora S. |
author_sort | Philips, Steven T. |
collection | PubMed |
description | 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 (A/E) 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 one week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (LSKs) normalized. Supplementation of imatinib with G-CSF 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. |
format | Online Article Text |
id | pubmed-4025985 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-40259852015-05-13 Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells Philips, Steven T. Hildenbrand, Zacariah L. Oravecz-Wilson, Katherine I. Foley, S. Blake Mgbemena, Victoria E. Ross, Theodora S. Oncogene Article 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 (A/E) 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 one week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (LSKs) normalized. Supplementation of imatinib with G-CSF 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. 2013-11-18 2014-11-13 /pmc/articles/PMC4025985/ /pubmed/24240679 http://dx.doi.org/10.1038/onc.2013.484 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Philips, Steven T. Hildenbrand, Zacariah L. Oravecz-Wilson, Katherine I. Foley, S. Blake Mgbemena, Victoria E. Ross, Theodora S. Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title | Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title_full | Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title_fullStr | Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title_full_unstemmed | Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title_short | Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells |
title_sort | towards a therapeutic reduction of imatinib refractory myeloproliferative neoplasm-initiating cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025985/ https://www.ncbi.nlm.nih.gov/pubmed/24240679 http://dx.doi.org/10.1038/onc.2013.484 |
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