H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients.
Kolja SchleichJulia KaseJan R DörrSaskia TrescherAnimesh BhattacharyaYong YuElizabeth M WailesDorothy N Y FanPhilipp LohneisMaja MilanovicAndrea LauDido LenzeMichael HummelBjoern ChapuyUlf LeserMaurice ReimannSoyoung LeeClemens A SchmittPublished in: Nature communications (2020)
Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles - such as cellular senescence - remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas - with and without defined genetic lesions - recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.
Keyphrases
- diffuse large b cell lymphoma
- epstein barr virus
- papillary thyroid
- mouse model
- clinical trial
- dna damage
- endothelial cells
- genome wide
- end stage renal disease
- case report
- squamous cell
- ejection fraction
- newly diagnosed
- healthcare
- stress induced
- poor prognosis
- chronic kidney disease
- gene expression
- primary care
- copy number
- randomized controlled trial
- oxidative stress
- transcription factor
- childhood cancer
- skeletal muscle
- peritoneal dialysis
- radiation therapy
- open label
- amino acid
- drug delivery
- high fat diet induced
- genome wide identification
- double blind
- single molecule
- study protocol
- rna seq
- combination therapy
- machine learning
- insulin resistance
- genetic diversity