BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage

Abstract

The inducible loss of BCL-XL in all cells of adult mice causes primary anemia due to apoptosis of erythroid and megakaryocytic cell populations. In contrast g-radiation plus loss of BCL-XL in all cells except hematopoietic cells causes secondary anemia resulting from kidney damage. AbstractStudies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis, but less is known about the roles of these proteins in adults, including in the 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 g-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 combinations with DNA damage-inducing drugs for cancer therapy.