BCL-XL exerts a protective role against anemia caused by radiation-induced kidney damage

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 gamma -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. SYNOPSIS image The pro-survival BCL-2 family member BCL-XL is critical for the survival of renal proximal tubular epithelial cells during radiation therapy in cancer patients. Genetic loss of BCL-XL, but not its pharmacological inhibition, causes fatal kidney damage and secondary anemia in adult mice after total body irradiation. Inducible loss of BCL-XL in all cells in adult mice causes primary anemia due to apoptosis of erythroid and megakaryocytic cell populations. gamma -radiation and BCL-XL deficiency in all non-hematopoietic cells cause secondary anemia resulting from kidney damage. gamma -radiation or DNA damage-inducing drugs in combination with specific BCL-XL inhibitor A1331852 is tolerated in mice.