Variegated clonality and rapid emergence of new molecular lesions in xenografts of acute lymphoblastic leukemia are associated with drug resistance

Autor: Norihiko Kawamata, Maximilian Mossner, Seishi Ogawa, Rachael A. Papa, Motohiro Kato, Nils H. Thoennissen, Masashi Sanada, Daniel Nowak, Ryoko Okamoto, H. Phillip Koeffler, Marion Klaumünzer, Tadayuki Akagi, Richard B. Lock, Johann Christoph Jann, Glenn M. Marshall, Verena Nowak, Natalia L. M. Liem, Wolf-Karsten Hofmann
Rok vydání: 2014
Předmět:
Male
Cancer Research
Biopsy
Gene Dosage
Drug resistance
Mice
SCID
medicine.disease_cause
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Dexamethasone
Mice
Polymorphism (computer science)
Mice
Inbred NOD
Peptide Synthases
Mutation
Massive parallel sequencing
Cytarabine
Hematology
DNA
Neoplasm
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasm Proteins
Vincristine
Radiation Chimera
Disease Progression
Neoplastic Stem Cells
Heterografts
Female
medicine.drug
Antineoplastic Agents
Biology
Polymorphism
Single Nucleotide
Article
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Deoxycytidine Kinase
Genetics
medicine
Animals
Humans
Allele
Molecular Biology
Gene
Cell Biology
Sequence Analysis
DNA
Clone Cells
genomic DNA
Methotrexate
Drug Resistance
Neoplasm
Immunology
Cancer research
Neoplasm Transplantation
Zdroj: Experimental hematology. 43(1)
ISSN: 1873-2399
Popis: 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.
Databáze: OpenAIRE
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