BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition

Cihangir Duy, Christian Hurtz, Seyedmehdi Shojaee, Leandro Cerchietti, Huimin Geng, Srividya Swaminathan, Lars Klemm, Soo Mi Kweon, Rahul Nahar, Melanie Braig, Eugene Park, Yong Mi Kim, Wolf Karsten Hofmann, Sebastian Herzog, Hassan Jumaa, H. Phillip Koeffler, J. Jessica Yu, Nora Heisterkamp, Thomas G. Graeber, Hong WuB. Hilda Ye, Ari Melnick, Markus Müschen

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134 Scopus citations

Abstract

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.

Original languageEnglish (US)
Pages (from-to)384-391
Number of pages8
JournalNature
Volume473
Issue number7347
DOIs
StatePublished - May 19 2011

ASJC Scopus subject areas

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    Duy, C., Hurtz, C., Shojaee, S., Cerchietti, L., Geng, H., Swaminathan, S., Klemm, L., Kweon, S. M., Nahar, R., Braig, M., Park, E., Kim, Y. M., Hofmann, W. K., Herzog, S., Jumaa, H., Koeffler, H. P., Yu, J. J., Heisterkamp, N., Graeber, T. G., ... Müschen, M. (2011). BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature, 473(7347), 384-391. https://doi.org/10.1038/nature09883