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

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

169 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
Pages (from-to)	384-8
Number of pages	5
Journal	Nature
Volume	473
Issue number	7347
DOIs	https://doi.org/10.1038/nature09883
State	Published - May 19 2011

Keywords

ADP-Ribosylation Factor 1/metabolism
Animals
Cell Survival/drug effects
DNA-Binding Proteins/biosynthesis
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl/antagonists & inhibitors
Gene Expression Regulation, Neoplastic/drug effects
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Protein Kinase Inhibitors/pharmacology
Proto-Oncogene Proteins c-bcl-6
Transcription, Genetic
Tumor Suppressor Protein p53/metabolism

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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), 384-8. 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.",

keywords = "ADP-Ribosylation Factor 1/metabolism, Animals, Cell Survival/drug effects, DNA-Binding Proteins/biosynthesis, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl/antagonists & inhibitors, Gene Expression Regulation, Neoplastic/drug effects, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins c-bcl-6, Transcription, Genetic, Tumor Suppressor Protein p53/metabolism",

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",

year = "2011",

month = may,

day = "19",

doi = "10.1038/nature09883",

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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. 384-8. https://doi.org/10.1038/nature09883

TY - JOUR

T1 - BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition

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

N2 - 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.

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.

KW - ADP-Ribosylation Factor 1/metabolism

KW - Animals

KW - Cell Survival/drug effects

KW - DNA-Binding Proteins/biosynthesis

KW - Drug Resistance, Neoplasm

KW - Fusion Proteins, bcr-abl/antagonists & inhibitors

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Humans

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Protein Kinase Inhibitors/pharmacology

KW - Proto-Oncogene Proteins c-bcl-6

KW - Transcription, Genetic

KW - Tumor Suppressor Protein p53/metabolism

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U2 - 10.1038/nature09883

DO - 10.1038/nature09883

M3 - Article

C2 - 21593872

SN - 0028-0836

VL - 473

SP - 384

EP - 388

JO - Nature

JF - Nature

IS - 7347

ER -

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

Abstract

Keywords

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