Erratum:BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome (Journal of Clinical Investigation (2020) 130:1 (171-188) DOI: 10.1172/JCI126863)

During the preparation of this manuscript, the same sample was inadvertently included for the +/L1002P and +/– images in Figure 2E. The authors were able to use the original samples to prepare a corrected version. The correct figure is below. The description in Methods for this panel has also been corrected, as below: To assess the mitotic index of spontaneous lymphatic tumors, mitotic cells were visualized by IF labelling of at least 1 paraffin section for pHH3 (EMD Millipore, catalog 06-570), as described (6, 46). The online version of the article has been updated with the corrected information. The authors regret the errors

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1(L1012P) mutation in mice (BubR1(L1002P)) and combined it with 2 other MVA variants, BUBR1(X753) and BUBR1(H), generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1(X753/L1002P) and BubR1(H/X753) mice died prematurely, BubR1(H/L1002P) mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1(H/H) mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations

Two-Step Senescence-Focused Cancer Therapies

Damaged cells at risk of neoplastic transformation can be neutralized by apoptosis or engagement of the senescence program, which induces permanent cell-cycle arrest and a bioactive secretome that is implicated in tumor immunosurveillance. While from an evolutionary perspective senescence is beneficial in that it protects against malignancies, the accumulation of senescent cells in tissues and organs with aging and at sites of various pathologies is largely detrimental. Because induction of senescence in cancer cells is emerging as a therapeutic concept, it will be important to consider these detrimental effects, including tumor-promoting properties that may drive the formation of secondary tumors or cancer relapse. In this review we discuss the complex relationship between senescence and cancer, and highlight important considerations for therapeutics