We analyzed regulation of the prosurvival Bcl-2 homologue A1, following T-cell receptor (TCR) or cytokine receptor engagement. Activation of CD4 + or CD8 + T cells by antigenic peptides induced an early but transient IL-2-independent expression of A1 and Bcl-xl mRNA and proteins, whereas expression of Bcl-2 was delayed and required IL-2. Cytokines such as IL-2, IL-4, IL-7 or IL-15 prevented apoptosis of activated T cells that effect being associated with the maintenance of Bcl-2, but not of A1 expression. However, restimulation of activated or posteffector T cells with antigenic peptide strongly upregulated A1 mRNA and maintained A1 protein expression. IL-4, IL-7 or IL-15 also prevented cell death of naive T cells. In those cells, cytokines upregulated Bcl-2, but not A1 expression. Therefore, in naive, activated and posteffector T cells, expression of A1 is dependent on TCR but not on cytokine receptor engagement, indicating that A1 is differently regulated from Bcl-xl and Bcl-2.

No abstract

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

No abstract

1The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-2 penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been 3 modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We 4 describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited 5

Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.

Untransformed HTLV-1 positive CD41 cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4 1 cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4 1 but not uninfected CD4 1 or CD8 1 clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4 1 cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression.HTLV-1 is the deltaretrovirus that causes adult T-cell leukemia/lymphoma (ATLL) 1 and tropical spastic paraparesis/ HTLV-associated myelopathy (TSP/HAM).2 HTLV-1 infection also leads to chronic immunosuppression. Circulating leukocytes from infected individuals have a reduced capacity to respond to recall antigens 3 and HTLV-1 carriers have an increased incidence of infectious diseases, such as infective dermatitis, infection with strongyloides stercoralis, 4 scabies and pneumocystis jirovecii. Pathogenesis of HTLV-1 infection relies in part on the persistent clonal expansion of infected cells 5 that mainly depends on infected CD4 þ cell cycling and on the prevention of infected CD8 þ cell death. 6,7 Clonal expansion allows for virus storage and persistence, virus dissemination in body compartments, virus and cellular genetic instability, impairment of anti-HTLV-1 cellular immune response, tissues damage and malignant transformation (reviewed in Ref. ). Telomeres, the chromosome extremities, are protected by specialized factors that prevent chromosomal instability and subsequent gross rearrangement of the genome (reviewed in Ref. 8 ). The telomere capping factors include a complex of six proteins specifically bound to telomeric DNA, called shelterin, the telomeric RNA as well as general factors involved in DNA damage response and replication. The elongation of telomeric DNA depends on telomerase, a reverse transcriptase specifically

In spring 2020, governments of many countries implemented lockdown measures to prevent the spread of the COVID-19 pandemic. Worldwide, the pandemic forced about 1.5 billion children to stay at home for several weeks and to experience homeschooling. The objective of this study was to assess the variation in stress levels and associated factors in school-aged children in France during the first COVID-19 lockdown. A cross-sectional study using an online questionnaire was designed by an interdisciplinary team involving hospital child psychiatrists and school doctors. Between 15 June and 15 July 2020, Educational Academy of Lyon (France) invited the parents of school-aged children to participate in this survey. The first part of the questionnaire concerned the children with data on lockdown conditions, socio-demographic data, daily rhythms (eating and sleeping), perceived stress variations, and feelings. The second part assessed parental perspectives on their child’s psychological state and use of the mental health care system. Multivariate logistic regression was performed to identify factors associated with stress variation (increased or decreased). A total of 7218 questionnaires were fully completed by children from elementary school to high school with a balanced sex ratio. In summary, 29% of children reported a higher stress level during the lockdown, 34% reported a lower stress level, and 37% reported no stress variation in the usual situation prior to COVID-19. Parents were most often able to identify signs of increased stress levels in their children. The most influential factors in the variation of stress for children were academic pressure, family relationships, and fear of being infected or infecting a family member with SARS-CoV-2. Our study underlines the high impact of school attendance stressors on children in usual conditions and encourages vigilance for children whose stress levels have decreased during the lockdown but who may have increased difficulty re-exposing themselves upon deconfinement.