Targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T lymphocyte proliferation, and T cells showed enhanced IL-2 responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia, suggesting that p27 and Rb function in the same regulatory pathway. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of secondary ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired.

Abstractp27 Kip1 is a candidate human tumour-suppressor protein, because it is able to inhibit cyclindependent kinases and block cell proliferation [1][2][3][4][5] . Abnormally low levels of the p27 protein are frequently found in human carcinomas, and these low levels correlate directly with both histological aggressiveness and patient mortality [6][7][8][9][10] . However, it has not been possible to establish a causal link between p27 and tumour suppression, because only rare instances of homozygous inactivating mutations of the p27 gene have been found in human tumours [11][12][13][14] . Thus, p27 Kip1 does not fulfill Knudson's 'two-mutation' criterion for a tumour suppressor gene 15 . Here we show that both p27 nullizygous and p27 heterozygous mice are predisposed to tumours in multiple tissues when challenged with g-irradiation or a chemical carcinogen. Therefore p27 is a multipletissue tumour suppressor in mice. Molecular analyses of tumours in p27 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Hence, p27 is haplo-insufficient for tumour suppression. The assumption that null mutations in tumour-suppressor genes are recessive excludes those genes that exhibit haplo-insufficiency.Tumour-suppressor proteins affect several cellular pathways, such as those controlling proliferation, apoptosis, differentiation and genomic integrity. Consequently, the identification of a tumour-suppressor gene is usually established genetically rather than by any particular functional criterion. The common operational definition of a tumoursuppressor gene requires the demonstration of mutations of both copies of a candidate gene in tumours 15 . Genetic and physical mapping of bi-allelic tumour specific mutations allows localization of tumour-suppressor genes, and provides evidence for a causal link between mutations in those genes and tumorigenesis. This approach has successfully demonstrated the tumour-suppressor function of the retinoblastoma protein (Rb), p53, INK4a, and others [16][17][18] . However, we show here that this definition is too restrictive because it excludes tumour suppressors such as p27 Kip1 that exhibit haplo-insufficiency.We studied the tumour-suppressor function of p27 Kip1 by examining the susceptibility of p27-deficient mice to tumorigenesis induced by two different DNA-damaging agents, gCorrespondence and requests for materials should be addressed to M.L.F. (mfero@fhcrc.org). -ethyl-N-nitrosourea (ENU). p27 −/− mice showed decreased tumour-free survival following g-irradiation compared with p27 +/+ controls (Fig. 1a). p27 +/− mice showed an intermediate sensitivity (see below). Thymic lymphomas were the most frequent tumours in wild-type mice (incidence 0.07), but their frequency was not significantly increased in p27 −/− animals (incidence 0.17). The increased mortality of p27-null mice was mainly due to the development of pituitary tumours and intestinal adenomas (Fig. 2). A separate group of mice was injected with a single dose of ENU, and again p27-nu...

Risk factors for grades 2-4 acute graftversus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD. (Blood. 2011;117(11):3214-3219) IntroductionDuring the past 3 decades, several studies have identified risk factors associated with the development of acute and chronic graft-versus-host disease (GVHD). 1 In these studies, acute GVHD generally referred to disease manifestations that occurred within the first 100 days after hematopoietic cell transplantation (HCT), [2][3][4] and chronic GVHD referred to disease manifestations that were present after day 100. 5 The most consistently reported factors significantly associated with an increased risk of grades 2-4 acute GVHD were recipient human leukocyte antigen (HLA) mismatching with the donor, 6-8 alloimmunization of the donor, 9-12 the use of a female donor for male recipients, 9,11-13 and older patient age. 11,13,14 Less consistently reported risk factors have included prior cytomegalovirus infection in the recipient, 14,15 higher intensity of the conditioning regimen (irradiation), 12,14 donor age, 16 and grafting with growth factor-mobilized blood cells. 14,17 For chronic GVHD, the most consistently reported risk factors include prior acute GVHD, 18-20 grafting with growth factor-mobilized blood cells, 17,21,22 the use of a female donor for male recipients, 19,20,23 older patient age, 18-20,23 and mismatched and unrelated donors. 20,24 The objective of the current study was to compare risk factor profiles for grades 2-4 acute and chronic GVHD. For this purpose, we used diagnostic criteria recommended by the National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. 25 According to these criteria, acute and chronic GVHD are distinguished by differences in clinical manifestations and...

Hearing loss is most often the result of hair-cell degeneration due to genetic abnormalities or ototoxic and traumatic insults. In the postembryonic and adult mammalian auditory sensory epithelium, the organ of Corti, no hair-cell regeneration has ever been observed. However

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