title: Variegated clonality and rapid emergence of new molecular lesions in xenografts of acute lymphoblastic leukemia are associated with drug resistance.
abstract: The use of genome-wide copy-number analysis and massive parallel sequencing has revolutionized the understanding of the clonal architecture of pediatric acute lymphoblastic leukemia (ALL) by demonstrating that this disease is composed of highly variable clonal ancestries following the rules of Darwinian selection. The current study aimed to analyze the molecular composition of childhood ALL biopsies and patient-derived xenografts with particular emphasis on mechanisms associated with acquired chemoresistance. Genomic DNA from seven primary pediatric ALL patient samples, 29 serially passaged xenografts, and six in vivo selected chemoresistant xenografts were analyzed with 250K single-nucleotide polymorphism arrays. Copy-number analysis of non-drug-selected xenografts confirmed a highly variable molecular pattern of variegated subclones. Whereas primary patient samples from initial diagnosis displayed a mean of 5.7 copy-number alterations per sample, serially passaged xenografts contained a mean of 8.2 and chemoresistant xenografts a mean of 10.5 copy-number alterations per sample, respectively. Resistance to cytarabine was explained by a new homozygous deletion of the DCK gene, whereas methotrexate resistance was associated with monoallelic deletion of FPGS and mutation of the remaining allele. This study demonstrates that selecting for chemoresistance in xenografted human ALL cells can reveal novel mechanisms associated with drug resistance.
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States; Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany. Electronic address: daniel.nowak@medma.uni-heidelberg.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nowak
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Natalia L M
authors.initials: NL
authors.lastname: Liem
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mossner
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Klaumünzer
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Papa
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States; Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Nowak
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
authors.forename: Johann C
authors.initials: JC
authors.lastname: Jann
authors.affiliation: Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Akagi
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kawamata
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States.
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA, United States; National University of Singapore, Singapore, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy; D002999:Clone Cells / Q000473:pathology*; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000235:genetics; D003842:Deoxycytidine Kinase / Q000235:genetics; D003907:Dexamethasone / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D064593:Heterografts; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010453:Peptide Synthases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011828:Radiation Chimera; D017422:Sequence Analysis, DNA; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D003561:Cytarabine; D014750:Vincristine; D003907:Dexamethasone; D003842:Deoxycytidine Kinase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate