Abnormal telomere metabolism in Fanconi's anaemia correlates with genomic instability and the probability of developing severe aplastic anaemia
Xiaxin Li
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorFrançois Leteurtre
Hemato-Immunology Research Laboratory, DRM, DSV, CEA,
Search for more papers by this authorVanderson Rocha
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorPhilippe Guardiola
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorGwenaëlle L. E. Roux
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Hemato-Immunology Research Laboratory, DRM, DSV, CEA,
Search for more papers by this authorPauline De La Salmonière
Medical Biostatistcs Department, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75475 Paris, France
Search for more papers by this authorPatrice Richard
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorEliane Gluckman
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorXiaxin Li
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorFrançois Leteurtre
Hemato-Immunology Research Laboratory, DRM, DSV, CEA,
Search for more papers by this authorVanderson Rocha
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorPhilippe Guardiola
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorGwenaëlle L. E. Roux
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Hemato-Immunology Research Laboratory, DRM, DSV, CEA,
Search for more papers by this authorPauline De La Salmonière
Medical Biostatistcs Department, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75475 Paris, France
Search for more papers by this authorPatrice Richard
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorEliane Gluckman
Bone Marrow Biology Laboratory, DRED University, Paris, and Bone Marrow Transplant Unit AP/HP,
Search for more papers by this authorPresent addresses: Indiana University School of Medicine, Indianapolis, IN, USA.†CEA Saclay, France.‡IGR, Villejuif, France.
Abstract
Summary. Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure and a susceptibility to cancer. Haematopoietic stem cell transplantation is the only curative method for restoring normal haematopoiesis, and survival is improved if the transplant is carried out before severe complications occur. However, the evolution of FA is difficult to predict because of the absence of known prognostic factors and the unknown function of the genes involved. In studying 71 FA patients, a correlation was found between severe aplastic anaemia (SAA) and the individual annual telomere-shortening rate (IATSR) in peripheral blood mononuclear cells (P < 10−3). Spontaneous apoptosis was highest in SAA patients or patients with high IATSR (> 200 bp/year) (P < 0·01, n = 18). Univariate and multivariate analyses showed that significant relative risks for evolution towards SAA were high IATSR (P < 10−4), and that a high number of chromosome breakages occurred in the presence of nitrogen mustard (P < 0·001). A high IATSR was also associated with an increased frequency of malignancy (P < 0·01). Thus, these biological parameters were related to the spontaneous evolution of FA and could be used as prognostic factors. These data indicated that telomeres might play a role in the evolution of bone marrow failure and malignant transformation in FA.
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