title: Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance.
abstract: Malignant transformation is a multistep process that is dictated by the acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. However, it remains unclear whether the genetic events that occur during transformation are similar in mice and humans. To address that, we chose several transgenic mouse models of hematopoietic malignancies and identified acquired mutations in these mice by means of targeted re-sequencing of known cancer-associated genes as well as whole exome sequencing. We found that mutations that are typically found in acute myeloid leukemia or T cell acute lymphoblastic leukemia patients are also common in mouse models of the respective disease. Moreover, we found that the most frequent mutations found in a mouse model of lymphoma occur in a set of epigenetic modifier genes, implicating this pathway in the generation of lymphoma. These results demonstrate that genetically engineered mouse models (GEMM) mimic the genetic evolution of human cancer and serve as excellent platforms for target discovery and validation.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Liat
authors.initials: L
authors.lastname: Goldberg
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Sheryl M
authors.initials: SM
authors.lastname: Gough
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Fan
authors.initials: F
authors.lastname: Lee
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Dang
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yuelin J
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Sven
authors.initials: S
authors.lastname: Bilke
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Center for Medical Education/Department of hematology, Hokkaido University Graduate School of Medicine Hokkaido, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onozawa
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jo Chung
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Peter D
authors.identifier: http://orcid.org/0000-0001-5686-9969
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D009154:Mutation