PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.

Abstract

Bone marrow failure is a severe complication of human telomere biology disorders and predisposes individuals to secondary leukemia. A deeper understanding of this process could offer significant clinical benefits. Using a preclinical mouse model deficient in the RNA component of the telomerase (mTerc), we demonstrate that bone marrow failure results from excessive apoptosis, predominantly mediated by the pro-apoptotic p53 target PUMA. Genetic ablation of Puma alleviates hematological phenotypes and reduces the risk of lethal bone marrow failure while preserving genomic stability. Mechanistically, PUMA deficiency decreases the sensitivity of hematopoietic cells to lethal stressors, including critically short telomeres. As a consequence, reduced compensatory turnover of hematopoietic progenitors slows down telomere shortening at the population level, delays stem cell exhaustion, and diminishes the acquisition of somatic mutations - ultimately preventing neoplastic transformation. Elevated expression of both p53 and PUMA is also observed in the bone marrow from patients with telomere biology disorders. While apoptosis resistance is traditionally associated with malignant transformation, our findings provide evidence that selective inhibition of PUMA-mediated apoptosis may represent a viable therapeutic strategy to prevent or delay leukemic transformation in this patient population.