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 Wu; B. Hilda Ye; Ari Melnick; Markus Müschen

doi:10.1038/nature09883

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

Cell Biology

Research output: Contribution to journal › Article › peer-review

164 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 language	English (US)
Pages (from-to)	384-391
Number of pages	8
Journal	Nature
Volume	473
Issue number	7347
DOIs	https://doi.org/10.1038/nature09883
State	Published - May 19 2011

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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

Duy, C, Hurtz, C, Shojaee, S, Cerchietti, L, Geng, H, Swaminathan, S, Klemm, L, Kweon, SM, Nahar, R, Braig, M, Park, E, Kim, YM, Hofmann, WK, Herzog, S, Jumaa, H, Koeffler, HP, Yu, JJ, Heisterkamp, N, Graeber, TG, Wu, H, Ye, BH, Melnick, A & Müschen, M 2011, 'BCL6 enables Ph⁺ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition', Nature, vol. 473, no. 7347, pp. 384-391. https://doi.org/10.1038/nature09883

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title = "BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition",

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.",

author = "Cihangir Duy and Christian Hurtz and Seyedmehdi Shojaee and Leandro Cerchietti and Huimin Geng and Srividya Swaminathan and Lars Klemm and Kweon, {Soo Mi} and Rahul Nahar and Melanie Braig and Eugene Park and Kim, {Yong Mi} and Hofmann, {Wolf Karsten} and Sebastian Herzog and Hassan Jumaa and Koeffler, {H. Phillip} and Yu, {J. Jessica} and Nora Heisterkamp and Graeber, {Thomas G.} and Hong Wu and Ye, {B. Hilda} and Ari Melnick and Markus M{\"u}schen",

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AU - Duy, Cihangir

AU - Hurtz, Christian

AU - Shojaee, Seyedmehdi

AU - Cerchietti, Leandro

AU - Geng, Huimin

AU - Swaminathan, Srividya

AU - Klemm, Lars

AU - Kweon, Soo Mi

AU - Nahar, Rahul

AU - Braig, Melanie

AU - Park, Eugene

AU - Kim, Yong Mi

AU - Hofmann, Wolf Karsten

AU - Herzog, Sebastian

AU - Jumaa, Hassan

AU - Koeffler, H. Phillip

AU - Yu, J. Jessica

AU - Heisterkamp, Nora

AU - Graeber, Thomas G.

AU - Wu, Hong

AU - Ye, B. Hilda

AU - Melnick, Ari

AU - Müschen, Markus

PY - 2011/5/19

Y1 - 2011/5/19

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AB - 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.

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

Abstract

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