Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias
| Autor: | Anneleen Daemen, Jasmine C. Wong, Xinyue Wang, Joy Nakitandwe, Anica M. Wandler, Kevin Shannon, Monique Dail, Jinghui Zhang, Lauren K. Meyer, Benjamin J. Huang, Qing Li, Deepak Sampath, Barry S. Taylor, James R. Downing |
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| Přispěvatelé: | Beier, David R |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Drug Resistance Cancer Treatment Gene Expression QH426-470 medicine.disease_cause Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Hematologic Cancers and Related Disorders Database and Informatics Methods Mice 0302 clinical medicine Medicine and Health Sciences 2.1 Biological and endogenous factors Aetiology Genetics (clinical) Cancer Pediatric 0303 health sciences Mutation Tumor Mammalian Genomics Hematology Genomics Animal Models 3. Good health Oncology Experimental Organism Systems 5.1 Pharmaceuticals KRAS Development of treatments and therapeutic interventions Sequence Analysis Biotechnology Research Article Lineage (genetic) Childhood Leukemia Pediatric Cancer Bioinformatics Mutagenesis (molecular biology technique) Mouse Models Biology Research and Analysis Methods Cell Line Clonal Evolution Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Germline mutation Rare Diseases Model Organisms Insertional Cell Line Tumor Leukemias medicine Genetics Point Mutation Animals Humans Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Chromosome Aberrations Genetic heterogeneity Animal Human Genome Cancers and Neoplasms Biology and Life Sciences medicine.disease Disease Models Animal Mutagenesis Insertional Orphan Drug Mutagenesis Animal Genomics Drug Resistance Neoplasm Disease Models Cancer research Animal Studies Neoplasm Somatic Mutation Carcinogenesis Sequence Alignment 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 15, Iss 6, p e1008168 (2019) PLoS Genetics PLoS genetics, vol 15, iss 6 |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance. Author summary A lack of predictive cancer models is a major bottleneck for prioritizing new anti-cancer drugs for clinical trials. We comprehensively profiled a panel of primary mouse T lineage leukemias initiated by insertional mutagenesis and found remarkable similarities with human T-ALL in regard to overall mutational burden, the occurrence of specific somatic mutations and large chromosomal alterations, and concordant gene expression signatures. We observed frequent duplication of the Kras oncogene with loss of the normal allele, which has potential therapeutic implications that merit further investigation in human leukemia and in other preclinical models. Mutations identified in mouse leukemias that relapsed after in vivo treatment with signal transduction inhibitors were also observed in relapsed human T-ALL, indicating that this model system can be utilized to investigate strategies for overcoming intrinsic and acquired drug resistance. Finally, preclinical models similar to the one described here that are characterized by a normal endogenous tumor microenvironment and intact immune system will become increasingly important for testing immunotherapy approaches for human cancer. |
| Databáze: | OpenAIRE |
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