Journal Article

DKFZ-2025-01724

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.

Molnar, C. ; Rajak, J. ; Weiss, J. M. ; Gonzalez-Menendez, I. ; Andrieux, G. ; Schreiber, F. ; Kornemann, E.-M. ; Wendeburg, L. ; Göhring, G. ; Strahm, B. ; Beier, F. ; Steinemann, D. ; Börries, M.DKFZ* ; Rudelius, M. ; Quintanilla-Martinez, L. ; Niemeyer, C. M.DKFZ* ; Niewisch, M. R. ; Labi, V. ; Bohler, S. ; Erlacher, M.DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41418-025-01557-w

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.

Note: epub

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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