A therapeutically targetable mechanism of BCR-ABL - Independent imatinib resistance in chronic myeloid leukemia

Leyuan Ma, Yi Shan, Robert Bai, Liting Xue, Christopher A. Eide, Jianhong Ou, Lihua J. Zhu, Lloyd Hutchinson, Jan Cerny, Hanna Jean Khoury, Zhi Sheng, Brian J. Druker, Shaoguang Li, Michael R. Green

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Abstract

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 upregulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCh, 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.

Original languageEnglish (US)
Article number252ra121
JournalScience translational medicine
Volume6
Issue number252
DOIs
StatePublished - Sep 3 2014

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ASJC Scopus subject areas

  • Medicine(all)

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Ma, L., Shan, Y., Bai, R., Xue, L., Eide, C. A., Ou, J., Zhu, L. J., Hutchinson, L., Cerny, J., Khoury, H. J., Sheng, Z., Druker, B. J., Li, S., & Green, M. R. (2014). A therapeutically targetable mechanism of BCR-ABL - Independent imatinib resistance in chronic myeloid leukemia. Science translational medicine, 6(252), [252ra121]. https://doi.org/10.1126/scitranslmed.3009073