Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Jan A. Burger; Dan A. Landau; Amaro Taylor-Weiner; Ivana Bozic; Huidan Zhang; Kristopher Sarosiek; Lili Wang; Chip Stewart; Jean Fan; Julia Hoellenriegel; Mariela Sivina; Adrian M. Dubuc; Cameron Fraser; Yulong Han; Shuqiang Li; Kenneth J. Livak; Lihua Zou; Youzhong Wan; Sergej Konoplev; Carrie Sougnez; Jennifer R. Brown; Lynne V. Abruzzo; Scott L. Carter; J. Keating Michael; Matthew S. Davids; William G. Wierda; Kristian Cibulskis; Thorsten Zenz; Lillian Werner; Paola Dal Cin; Peter Kharchencko; Donna Neuberg; Hagop Kantarjian; Eric Lander; Stacey Gabriel; Susan O'Brien; Anthony Letai; David A. Weitz; Martin A. Nowak; Gad Getz; Catherine J. Wu

doi:10.1038/ncomms11589

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Jan A. Burger, Dan A. Landau, Amaro Taylor-Weiner, Ivana Bozic, Huidan Zhang, Kristopher Sarosiek, Lili Wang, Chip Stewart, Jean Fan, Julia Hoellenriegel, Mariela Sivina, Adrian M. Dubuc, Cameron Fraser, Yulong Han, Shuqiang Li, Kenneth J. Livak, Lihua Zou, Youzhong Wan, Sergej Konoplev, Carrie SougnezJennifer R. Brown, Lynne V. Abruzzo, Scott L. Carter, J. Keating Michael, Matthew S. Davids, William G. Wierda, Kristian Cibulskis, Thorsten Zenz, Lillian Werner, Paola Dal Cin, Peter Kharchencko, Donna Neuberg, Hagop Kantarjian, Eric Lander, Stacey Gabriel, Susan O'Brien, Anthony Letai, David A. Weitz, Martin A. Nowak, Gad Getz, Catherine J. Wu

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

271 Scopus citations

Abstract

Resistance to the Brutonâ € s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-Targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

Original language	English (US)
Article number	11589
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11589
State	Published - May 20 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Clinical Trials Office

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10.1038/ncomms11589

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Burger, J. A., Landau, D. A., Taylor-Weiner, A., Bozic, I., Zhang, H., Sarosiek, K., Wang, L., Stewart, C., Fan, J., Hoellenriegel, J., Sivina, M., Dubuc, A. M., Fraser, C., Han, Y., Li, S., Livak, K. J., Zou, L., Wan, Y., Konoplev, S., ... Wu, C. J. (2016). Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nature communications, 7, Article 11589. https://doi.org/10.1038/ncomms11589

Burger, JA, Landau, DA, Taylor-Weiner, A, Bozic, I, Zhang, H, Sarosiek, K, Wang, L, Stewart, C, Fan, J, Hoellenriegel, J, Sivina, M, Dubuc, AM, Fraser, C, Han, Y, Li, S, Livak, KJ, Zou, L, Wan, Y, Konoplev, S, Sougnez, C, Brown, JR, Abruzzo, LV, Carter, SL, Michael, JK, Davids, MS, Wierda, WG, Cibulskis, K, Zenz, T, Werner, L, Cin, PD, Kharchencko, P, Neuberg, D, Kantarjian, H, Lander, E, Gabriel, S, O'Brien, S, Letai, A, Weitz, DA, Nowak, MA, Getz, G & Wu, CJ 2016, 'Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition', Nature communications, vol. 7, 11589. https://doi.org/10.1038/ncomms11589

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title = "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition",

abstract = "Resistance to the Bruton{\^a} € s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-Targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.",

author = "Burger, {Jan A.} and Landau, {Dan A.} and Amaro Taylor-Weiner and Ivana Bozic and Huidan Zhang and Kristopher Sarosiek and Lili Wang and Chip Stewart and Jean Fan and Julia Hoellenriegel and Mariela Sivina and Dubuc, {Adrian M.} and Cameron Fraser and Yulong Han and Shuqiang Li and Livak, {Kenneth J.} and Lihua Zou and Youzhong Wan and Sergej Konoplev and Carrie Sougnez and Brown, {Jennifer R.} and Abruzzo, {Lynne V.} and Carter, {Scott L.} and Michael, {J. Keating} and Davids, {Matthew S.} and Wierda, {William G.} and Kristian Cibulskis and Thorsten Zenz and Lillian Werner and Cin, {Paola Dal} and Peter Kharchencko and Donna Neuberg and Hagop Kantarjian and Eric Lander and Stacey Gabriel and Susan O'Brien and Anthony Letai and Weitz, {David A.} and Nowak, {Martin A.} and Gad Getz and Wu, {Catherine J.}",

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doi = "10.1038/ncomms11589",

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T1 - Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

AU - Burger, Jan A.

AU - Landau, Dan A.

AU - Taylor-Weiner, Amaro

AU - Bozic, Ivana

AU - Zhang, Huidan

AU - Sarosiek, Kristopher

AU - Wang, Lili

AU - Stewart, Chip

AU - Fan, Jean

AU - Hoellenriegel, Julia

AU - Sivina, Mariela

AU - Dubuc, Adrian M.

AU - Fraser, Cameron

AU - Han, Yulong

AU - Li, Shuqiang

AU - Livak, Kenneth J.

AU - Zou, Lihua

AU - Wan, Youzhong

AU - Konoplev, Sergej

AU - Sougnez, Carrie

AU - Brown, Jennifer R.

AU - Abruzzo, Lynne V.

AU - Carter, Scott L.

AU - Michael, J. Keating

AU - Davids, Matthew S.

AU - Wierda, William G.

AU - Cibulskis, Kristian

AU - Zenz, Thorsten

AU - Werner, Lillian

AU - Cin, Paola Dal

AU - Kharchencko, Peter

AU - Neuberg, Donna

AU - Kantarjian, Hagop

AU - Lander, Eric

AU - Gabriel, Stacey

AU - O'Brien, Susan

AU - Letai, Anthony

AU - Weitz, David A.

AU - Nowak, Martin A.

AU - Getz, Gad

AU - Wu, Catherine J.

PY - 2016/5/20

Y1 - 2016/5/20

N2 - Resistance to the Brutonâ € s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-Targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

AB - Resistance to the Brutonâ € s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-Targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

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DO - 10.1038/ncomms11589

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Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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