A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia
Authors
Ma, LeyuanShan, Yi
Bai, Robert
Xue, Liting
Eide, Christopher A.
Ou, Jianhong
Zhu, Lihua Julie
Hutchinson, Lloyd
Cerny, Jan
Khoury, Hanna Jean
Sheng, Zhi
Druker, Brian J.
Li, Shaoguang
Green, Michael R.
UMass Chan Affiliations
Department of PathologyDivision of Hematology/Oncology, Department of Medicine
Program in Molecular Medicine
Program in Gene Function and Expression
Document Type
Journal ArticlePublication Date
2014-09-03Keywords
BioinformaticsCancer Biology
Hematology
Neoplasms
Oncology
Pathology
Therapeutics
Translational Medical Research
Metadata
Show full item recordAbstract
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.Source
L. 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 siteDOI
10.1126/scitranslmed.3009073Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44048PubMed ID
25186176Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1126/scitranslmed.3009073