Clappier E.,Institute Of Radiobiologie Cellulaire Et Moleculaire |
Clappier E.,Institute National Of La Sante Et Of La Recherche Medicale Unite 944 |
Clappier E.,University Paris Diderot |
Gerby B.,Institute Of Radiobiologie Cellulaire Et Moleculaire |
And 22 more authors.
Journal of Experimental Medicine | Year: 2011
Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle-and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse. © 2011 Clappier et al. Source
Poulain M.,French Atomic Energy Commission |
Poulain M.,Institute National Of La Sante Et Of La Recherche Medicale Unite 967 |
Poulain M.,University Paris - Sud |
Frydman N.,French Atomic Energy Commission |
And 19 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Context: The 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Pregnant women presenting a risk of genetic transmission may be treated with synthetic glucocorticoids such as dexamethasone (DEX) to prevent female fetus virilization. Objective: The aim of this study was to assess the potential deleterious effects of DEX exposure on fetal ovarian development. Settings: Human fetal ovaries, ranging from 8-11 weeks after fertilization, were harvested from material available after legally induced abortions. They were cultured in the absence or presence of DEX (2, 10, or 50 μM) over 14 d, and histological analyses were performed. Results: The glucocorticoid receptor NR3C1 was present and the signaling pathway active in the fetal ovary as demonstrated by the expression of NR3C1 target genes, such as PLZF and FKBP5, in response to DEX exposure. DEX decreased germ cell density at the 10 and 50 μM doses. Exposure to DEX, even at the highest dose, did not change oogonial proliferation as monitored by 5-bromo-2′-deoxyuridine incorporation and significantly increased the apoptotic rate, detected with cleaved caspase 3 staining. Interestingly, the expression of the prosurvival gene KIT was significantly decreased in the presence of DEX during the course of the culture. Conclusion: We have demonstrated for the first time that in vitro exposure to high doses of DEX impairs human fetal oogenesis through an increase in apoptosis. These data are of high importance, and additional epidemiological studies are required to investigate the female fertility of those women who have been exposed to DEX during fetal life. Copyright © 2012 by The Endocrine Society. Source
Barroca V.,Institute Of Radiobiologie Cellulaire Et Moleculaire |
Barroca V.,VU University Amsterdam |
Barroca V.,Institute National Of La Sante Et Of La Recherche Medicale Unite 967 |
Barroca V.,University Paris Diderot |
And 42 more authors.
Human Molecular Genetics | Year: 2012
Fanconi anemia (FA) is a human rare genetic disorder characterized by congenital defects, bone marrow (BM) failure and predisposition to leukemia. The progressive aplastic anemia suggests a defect in the ability of hematopoietic stem cells (HSC) to sustain hematopoieis. We have examined the role of the nuclear FA core complex gene Fancg in the functionality of HSC. In Fancg-/- mice, we observed a decay of long-term HSC and multipotent progenitors that account for the reduction in the LSK compartment containing primitive hematopoietic cells. Fancg-/- lymphoid and myeloid progenitor cells were also affected, and myeloid progenitors show compromised in vitro functionality. HSC from Fancg-/- mice failed to engraft and to reconstitute at short and long term the hematopoiesis in a competitive transplantation assay. Fancg-/- LSK cells showed a loss of quiescence, an impaired migration in vitro in response to the chemokine CXCL12 and a defective homing to the BM after transplantation. Finally, the expression of several key genes involved in self-renewal, quiescence and migration of HSC was dysregulated in Fancg-deficient LSK subset. Collectively, our data reveal that Fancg should play a role in the regulation of physiological functions of HSC. © The Author 2011. Published by Oxford University Press. All rights reserved. Source