A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia
Eide, Christopher A.
Zhu, Lihua Julie
Khoury, Hanna Jean
Druker, Brian J.
Green, Michael R.
UMass Chan AffiliationsDepartment of Pathology
Division of Hematology/Oncology, Department of Medicine
Program in Molecular Medicine
Program in Gene Function and Expression
Document TypeJournal Article
Translational Medical Research
MetadataShow full item record
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.
SourceL. 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). Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/44048
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