title: Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.
abstract: 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.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.|Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.|Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10065, USA.|New York Genome Center, New York, New York 10013, USA.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Landau
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Mathematics, Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.affiliation: Department of Physics, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang 110001, China.|Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Huidan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kristopher
authors.identifier: 0000-0002-4618-5085
authors.initials: K
authors.lastname: Sarosiek
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston Massachusetts 02115, USA.
authors.forename: Jean
authors.identifier: 0000-0002-0212-5451
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Han
authors.affiliation: Fluidigm Corporation, South San Francisco, California 94080, USA.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Fluidigm Corporation, South San Francisco, California 94080, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Livak
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Lihua
authors.identifier: 0000-0003-0686-3117
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Youzhong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lynne V
authors.identifier: 0000-0001-6113-7447
authors.initials: LV
authors.lastname: Abruzzo
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: National Center for Tumors and German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston Massachusetts 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kharchencko
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Donna
authors.identifier: 0000-0003-2566-3145
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lander
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Physics, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Weitz
authors.affiliation: Department of Mathematics, Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000369:Aged, 80 and over; D017209:Apoptosis; D054338:Cell Transdifferentiation; D060965:Clonal Evolution; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D054747:Histiocytic Sarcoma / Q000209:etiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012641:Selection, Genetic
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine