Mutational landscape of T-cell lymphoma in mice lacking the DNA mismatch repair gene Mlh1: no synergism with ionizing radiation.
Carcinogenesis
; 40(2): 216-224, 2019 04 29.
Article
em En
| MEDLINE
| ID: mdl-30721949
ABSTRACT
Biallelic germline mutations in the DNA mismatch repair gene MLH1 lead to constitutional mismatch repair-deficiency syndrome and an increased risk for childhood hematopoietic malignancies, including lymphoma and leukemia. To examine how Mlh1 dysfunction promotes lymphoma as well as the influence of ionizing radiation (IR) exposure, we used an Mlh1-/- mouse model and whole-exome sequencing to assess genomic alterations in 23 T-cell lymphomas, including 8 spontaneous and 15 IR-associated lymphomas. Exposure to IR accelerated T-cell lymphoma induction in the Mlh1-/- mice, and whole-exome sequencing revealed that IR exposure neither increased the number of mutations nor altered the mutation spectrum of the lymphomas. Frequent mutations were evident in genes encoding transcription factors (e.g. Ikzf1, Trp53, Bcl11b), epigenetic regulators (e.g. Suv420h1, Ep300, Kmt2d), transporters (e.g. Rangap1, Kcnj16), extracellular matrix (e.g. Megf6, Lrig1), cell motility (e.g. Argef19, Dnah17), protein kinase cascade (e.g. Ptpro, Marcks) and in genes involved in NOTCH (e.g. Notch1), and PI3K/AKT (e.g. Pten, Akt2) signaling pathways in both spontaneous and IR-associated lymphomas. Frameshift mutations in mononucleotide repeat sequences within the genes Trp53, Ep300, Kmt2d, Notch1, Pten and Marcks were newly identified in the lymphomas. The lymphomas also exhibited a few chromosomal abnormalities. The results establish a landscape of genomic alterations in spontaneous and IR-associated lymphomas that occur in the context of mismatch repair dysfunction and suggest potential targets for cancer treatment.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutação da Fase de Leitura
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Linfoma de Células T
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Mutação em Linhagem Germinativa
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Reparo de Erro de Pareamento de DNA
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Proteína 1 Homóloga a MutL
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article