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dc.contributor.authorMa, Leyuan
dc.contributor.authorShan, Yi
dc.contributor.authorBai, Robert
dc.contributor.authorXue, Liting
dc.contributor.authorEide, Christopher A.
dc.contributor.authorOu, Jianhong
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorHutchinson, Lloyd
dc.contributor.authorCerny, Jan
dc.contributor.authorKhoury, Hanna Jean
dc.contributor.authorSheng, Zhi
dc.contributor.authorDruker, Brian J.
dc.contributor.authorLi, Shaoguang
dc.contributor.authorGreen, Michael R.
dc.date2022-08-11T08:10:15.000
dc.date.accessioned2022-08-23T17:01:37Z
dc.date.available2022-08-23T17:01:37Z
dc.date.issued2014-09-03
dc.date.submitted2014-11-04
dc.identifier.citationL. Ma, Y. Shan, R. Bai, L. Xue, C. A. Eide, J. Ou, L. J. Zhu, L. Hutchinson, J. Cerny, H. J. Khoury, Z. Sheng, B. J. Druker, S. Li, M. R. Green, A therapeutically targetable mechanism of BCR-ABL–independent imatinib resistance in chronic myeloid leukemia. Sci. Transl. Med. 6, 252ra121 (2014). <a href="http://dx.doi.org/10.1126/scitranslmed.3009073">Link to article on publisher's site</a>
dc.identifier.issn1946-6234 (Linking)
dc.identifier.doi10.1126/scitranslmed.3009073
dc.identifier.pmid25186176
dc.identifier.urihttp://hdl.handle.net/20.500.14038/44048
dc.description.abstractResistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCeta, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25186176&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1126/scitranslmed.3009073
dc.subjectBioinformatics
dc.subjectCancer Biology
dc.subjectHematology
dc.subjectNeoplasms
dc.subjectOncology
dc.subjectPathology
dc.subjectTherapeutics
dc.subjectTranslational Medical Research
dc.titleA therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia
dc.typeJournal Article
dc.source.journaltitleScience translational medicine
dc.source.volume6
dc.source.issue252
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pgfe_pp/263
dc.legacy.embargo2014-11-12T00:00:00-08:00
dc.identifier.contextkey6324040
html.description.abstract<p>Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCeta, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.</p>
dc.identifier.submissionpathpgfe_pp/263
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDivision of Hematology/Oncology, Department of Medicine
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pages252ra121


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