BCL-XL exerts a protective role against anemia caused by radiation-induced kidney damage.
Kerstin BrinkmannPaul WaringStefan P GlaserVerena WimmerDenny L CottleMing Shen ThamDuong NhuLachlan WhiteheadAlex Rd DelbridgeGuillaume L LesseneIan M SmythMarco J HeroldGemma L KellyStephanie GrabowAndreas StrasserPublished in: The EMBO journal (2020)
Studies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis. However, little is known about the role(s) of these proteins in adults in response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL deficiency in erythroid cells. Unexpectedly, the combination of total body γ-irradiation (TBI) and genetic loss of Bcl-x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combination with DNA damage-inducing drugs for cancer therapy. Encouragingly, the combination of DNA damage-inducing anti-cancer therapy plus a BCL-XL inhibitor could be tolerated in mice, at least when applied sequentially.
Keyphrases
- cancer therapy
- dna damage
- radiation induced
- bone marrow
- oxidative stress
- chronic kidney disease
- traumatic brain injury
- drug delivery
- induced apoptosis
- gene expression
- cell cycle arrest
- stem cells
- radiation therapy
- mass spectrometry
- dna repair
- adipose tissue
- transcription factor
- endoplasmic reticulum stress
- endothelial cells
- single molecule
- signaling pathway
- young adults
- combination therapy
- high speed
- replacement therapy
- genome wide analysis