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

被引：281

作者：

Burger, Jan A. ^{[1
]}

Landau, Dan A. ^{[2
,3
,4
,5
]}

Taylor-Weiner, Amaro ^{[2
]}

Bozic, Ivana ^{[6
,7
]}

Zhang, Huidan ^{[8
,9
,10
]}

Sarosiek, Kristopher ^{[11
]}

Wang, Lili ^{[11
]}

Stewart, Chip ^{[2
]}

Fan, Jean ^{[12
]}

Hoellenriegel, Julia ^{[1
]}

Sivina, Mariela ^{[1
]}

Dubuc, Adrian M. ^{[13
,14
]}

Fraser, Cameron ^{[11
]}

Han, Yulong ^{[15
]}

Li, Shuqiang ^{[16
]}

Livak, Kenneth J. ^{[16
]}

Zou, Lihua ^{[2
]}

Wan, Youzhong ^{[11
]}

Konoplev, Sergej ^{[17
]}

Sougnez, Carrie ^{[2
]}

Brown, Jennifer R. ^{[11
]}

Abruzzo, Lynne V. ^{[17
]}

Carter, Scott L. ^{[2
]}

Keating, Michael J. ^{[1
]}

Davids, Matthew S. ^{[11
]}

Wierda, William G. ^{[1
]}

Cibulskis, Kristian ^{[2
]}

Zenz, Thorsten ^{[18
,19
]}

Werner, Lillian ^{[20
]}

Dal Cin, Paola ^{[13
,14
]}

Kharchencko, Peter ^{[12
]}

Neuberg, Donna ^{[20
]}

Kantarjian, Hagop ^{[1
]}

Lander, Eric ^{[2
]}

Gabriel, Stacey ^{[2
]}

O'Brien, Susan ^{[1
]}

Letai, Anthony ^{[11
]}

Weitz, David A. ^{[8
]}

Nowak, Martin A. ^{[6
,7
]}

Getz, Gad ^{[2
]}

Wu, Catherine J. ^{[2
,11
,21
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[2] Broad Inst, Cambridge, MA 02142 USA

[3] Weill Cornell Med, Dept Med, New York, NY 10065 USA

[4] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA

[5] New York Genome Ctr, New York, NY 10013 USA

[6] Harvard Univ, Dept Math, Program Evolutionary Dynam, Cambridge, MA 02138 USA

[7] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA

[8] Harvard Univ, Sch Engn & Appl Sci, Dept Phys, Cambridge, MA 02138 USA

[9] China Med Univ, Minist Publ Hlth, Key Lab Cell Biol, Dept Cell Biol, Shenyang 110001, Peoples R China

[10] China Med Univ, Key Lab Med Cell Biol, Minist Educ, Shenyang 110001, Peoples R China

[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[12] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[14] Harvard Univ, Sch Med, Boston, MA 02115 USA

[15] Xi An Jiao Tong Univ, Bioinspired Engn & Biomech Ctr, Xian 710049, Peoples R China

[16] Fluidigm Corp, San Francisco, CA 94080 USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[18] Natl Ctr Tumors, D-69121 Heidelberg, Germany

[19] German Canc Res Ctr, D-69121 Heidelberg, Germany

[20] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA

[21] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02215 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家科学基金会; 中国国家自然科学基金;

关键词：

B-CELL LYMPHOMA; IBRUTINIB RESISTANCE; MUTATIONS; CANCER; TUMOR; CLL; IMMUNODEFICIENCY; PROGRESSION; EXPRESSION; DISCOVERY;

D O I：

10.1038/ncomms11589

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Resistance to the Bruton'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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