Deletion of the p53 Target Gene PUMA Prevents Bone Marrow Failure in a Dyskeratosis Congenita Mouse Model

Dyskeratosis congenita (DC) belongs to the group of inherited bone marrow failure syndromes (IBMFS) and is characterized by premature telomere shortening caused by mutations in components of the telomerase or the shelterin complexes. The main cause of death in affected patients is hematopoietic failure, but there is also a 10-15% risk of malignant transformation into secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Critically short telomeres activate a DNA damage response with p53-mediated cell cycle inhibition, senescence and/or apoptosis, the latter mediated primarily by PUMA, a BCL-2 family member belonging to the group of pro-apoptotic BH3-only proteins and transcriptionally regulated by p53. Activation of p53 and expression of its target genes are critical for the exhaustion of hematopoietic stem cells (HSCs) in DC patients. Inactivation of the DNA damage checkpoint could possibly mitigate hematopoietic failure but poses a significant risk of genomic instability and leukemia. Based on our earlier mouse model of secondary leukemia (Genes Dev, 24(15):1602-7), we hypothesized that selective inhibition of p53-mediated apoptosis - while all other p53-checkpoint-induced pathways remain active - could both delay hematopoietic failure and prevent malignant transformation.We established a DC mouse model by serial transplantation of hematopoietic stem and progenitor cells (HSPCs) derived from generation 3 mTerc-/- (G3 mTerc-/-) mice lacking the RNA telome...

Source: Blood - November 21, 2018 Category: Hematology Authors: Erlacher, M., Molnar, C., Weiss, J. M., Bohler, S., Steinemann, D., Gohring, G., Villunger, A., Labi, V., Niemeyer, C., Egle, A. Tags: 508. Bone Marrow Failure: Inherited Bone Marrow Failure: Germline Genetic Disorders Source Type: research