Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

UNLABELLED Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. SIGNIFICANCE We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101

La déficience en Maged1 chez la souris entraîne une diminution de la production d'ocytocine par l'hypothalamus, provoque de l'obésité et altère les comportements sociaux et sexuels.

The MAGED1 gene is located on the X chromosome, it belongs to the group/category of type II MAGE genes , which are expressed in various tissues during embryonic development and in adult organism. Among the type II MAGE genes, NECDIN and MAGEL2 are probably the most studied because of their putative involvement in the etiology of the Prader-Willi syndrome. Indeed, these two genes are located in the 15q11-q13 region that is absent in most people with the Prader-Willi syndrome. The most striking feature of individuals suffering from Prader-Willi syndrome is their hyperphagic behavior which leads to the development of morbid obesity if their food intake is not controlled. To investigate the function of Maged1 in vivo, Maged1- mice were previously obtained by gene targeting in our laboratory. Curiously, as it is observed in people with the Prader-Willi syndrome, the Maged1- mutants exhibit hyperphagia and develop obesity, although this obesity is milder and appears later compared to what is observed in individuals suffering from Prader-Willi syndrome. Maged1- knockout mice have also behavioral defects similar to those observed in autistic individuals. Interestingly 25% of the people with Prader-Willi syndrome also develop autism. To characterize the autistic-like behaviors of the Maged1- knockout mice, we submitted these mice to a battery of tests. The Maged1- knockout mice exhibited a reduced sociability in the test of reciprocal social interactions. In the three chamber experiment, the Maged1- mutants remained at distance of the mouse stimulus and a concomitant reduction in direct social interactions was observed. Finally in the social memory test, the Maged1- knockout mice were unable to discriminate a new partner from a familiar one. The Maged1- mutants also displayed reduced ultrasonic communications during courtship behavior and a severe reduction of coital activity. Besides defects in social interactions and communications, Maged1- mutants are hypoactive and display anxiety-like behaviors such as exaggerated self-grooming. This association of behavioral defects allows us to propose Maged1- knockout mice as a new model of "autistic mice". Loss of function of Maged1 gene in mice also leads to a reduced production of mature oxytocin, while the precursor and intermediate forms of this neuropeptide are normally synthesized. The lack of mature oxytocin may explain some of the phenotypes displayed by the knockout mice. Indeed, oxytocin is known to be involved in the regulation of food intake, social behavior, anxiety and sexual behavior. To demonstrate the role of oxytocin in the altered behavior of the Maged1- mice, we showed that peripheral injection of oxytocin rescued the social memory of these animals. Altogether, our results demonstrate an essential role for Maged1 in the regulation of social and sexual behaviors as well as in the control of metabolism which are in part explained by the regulation of mature oxytocin production by Maged1.Le gène MAGED1 est localisé sur le chromosome X, il appartient à la catégorie des gènes MAGE de type II qui sont exprimés dans de nombreux tissus pendant le développement embryonnaire et également aux stades adultes. Parmi les gènes MAGE de type II, NECDIN et MAGEL2 sont probablement les plus étudiés en raison de leur implication probable dans le développement du syndrome de Prader-Willi. En effet, ces deux gènes se trouvent dans la région 15q11-q13 qui est absente chez la plupart des patients atteints du syndrome de Prader-Willi. Ces patients présentent entre autres une hyperphagie qui entraîne le développement d'une obésité morbide si la prise alimentaire n'est pas contrôlée chez ces individus. Afin d'étudier la fonction de Maged1 in vivo, des souris knock-out Maged1- ont été crées dans notre laboratoire. Curieusement, comme les personnes atteintes du syndrome de Prader-Willi, les souris Maged1- présentent de l’hyperphagie et développent aussi de l'obésité bien qu'elle soit plus légère et apparaisse plus tard que chez les patients atteints du syndrome de Prader-Willi. Les mutants Maged1- présentent également des troubles du comportement semblables à ce qui est observé chez certains autistes. Or les personnes atteintes du syndrome de Prader-Willi développent également de l'autisme dans 25 % des cas. Afin de caractériser les comportements autistiques des mutants Maged1-, nous avons soumis ces souris à une batterie de tests. Ainsi, les mutants Maged1- présentent une sociabilité réduite dans le test des interactions sociales réciproques. Dans l'expérience des trois chambres, les mutants Maged1- restent à distance de la souris stimulus et présentent une réduction des interactions sociales directes mesurées par le temps d'investigation olfactive du stimulus. Enfin, dans le test de la mémoire sociale, les mutants Maged1- sont incapables de discriminer un nouveau partenaire par rapport à un partenaire familier. Les mutants Maged1- présentent également une réduction des communications vocales ultrasoniques pendant la parade nuptiale et une activité coïtale très réduite. En plus de présenter des défauts au niveau des interactions sociales et de la communication, les mutants Maged1- ont également une activité motrice spontanée réduite, une augmentation de certains comportements répétitifs (activité d’auto-toilettage exagérée) et présentent certains comportements associés à l’anxiété. L’association de ces défauts comportementaux nous permet de proposer les souris Maged1- comme un nouveau modèle de « souris autiste ». La délétion de Maged1 in vivo entraîne également une diminution de la production d’ocytocine mature tandis que les formes précurseurs et intermédiaires de ce neuropeptide sont normalement synthétisées chez les souris Maged1- . Ce défaut d'ocytocine mature peut expliquer une partie des phénotypes que nous avons observés chez les souris knock-out Maged1-. En effet, l'ocytocine est impliquée dans la régulation de la prise alimentaire, dans la régulation des comportements sociaux, de l'anxiété et du comportement sexuel. Le rôle de l'ocytocine dans l’altération des comportements sociaux, a été démontré par le rétablissement de la mémoire sociale après administration périphérique d’ocytocine. L'ensemble de ces résultats démontre un rôle essentiel de Maged1 dans la régulation des comportements sociaux et sexuels ainsi que dans le contrôle du métabolisme qui s’explique en partie par le rôle de Maged1 dans la production d’ocytocine mature.(DOCMED02) -- FUNDP, 201

Effects of combined exposure of adult male mice to di-(2-ethylexyl)phthalate and nonylphenol on behavioral and neuroendocrine responses

International audienceThe present study evaluates the effects of adult exposure to low doses of a mixture of di-(2-ethylexyl)phthalate (DEHP) and nonylphenol (NP) on reproductive neuroendocrine function and behavior. The neural circuitry that processes male sexual behavior is tightly regulated by testosterone and its neural metabolite estradiol. In previous studies, we showed that adult exposure of mice to low doses of each of these widespread environmental contaminants resulted in altered sexual behavior, without any effect on the regulation of the gonadotropic axis. Here, adult C57BL/6J male mice were exposed to DEHP/NP (0.5 or 5 μg/kg body weight/day) for 4 weeks before starting the analyses. Mice treated with DEHP/NP at 0.5 μg/kg/day show altered olfactory preference, and fewer of them emit ultrasonic vocalization compared to the other treatment groups. These mice also exhibit a lower number of mounts and thrusts, increased locomotor activity and unaffected anxiety-state level, along with unaltered testosterone levels and kisspeptin system, a key regulator of the gonadotropic axis. Analysis of the neural circuitry that underlies sexual behavior showed that the number of cells expressing androgen and estrogen receptors is comparable between control and DEHP/NP-exposed males. The comparison of these data with those obtained in males exposed to each molecule separately highlights synergistic effects at the lower dose of contaminants of 0.5 μg/kg/day. In contrast, the effects previously observed for each molecule at 5 μg/kg/day were not detected. A detailed comparison of the effects triggered by separate or combined exposure to DEHP and NP is discussed

Effects of neural estrogen receptor beta deletion on social and mood-related behaviors and underlying mechanisms in male mice

International audienceEstradiol derived from neural aromatization of testosterone plays a key role in the organization and activation of neural structures underlying male behaviors. This study evaluated the contribution of the estrogen receptor (ER) β in estradiol-induced modulation of social and mood-related behaviors by using mice lacking the ERβ gene in the nervous system. Mutant males exhibited reduced social interaction with same-sex congeners and impaired aggressive behavior. They also displayed increased locomotor activity, and reduced or unaffected anxiety-state level in three paradigms. However, when mice were exposed to unescapable stress in the forced swim and tail suspension tests, they spent more time immobile and a reduced time in swimming and climbing. These behavioral alterations were associated with unaffected circadian and restraint stress-induced corticosterone levels, and unchanged number of tryptophan hydroxylase 2-immunoreactive neurons in the dorsal raphe. By contrast, reduced mRNA levels of oxytocin and arginine-vasopressin were observed in the bed nucleus of stria terminalis, whereas no changes were detected in the hypothalamic paraventricular nucleus. The neural ERβ is thus involved to different extent levels in social and mood-related behaviors, with a particular action on oxytocin and arginine-vasopressin signaling pathways of the bed nucleus of stria terminalis, yet the involvement of other brain areas cannot be excluded

Mécanismes neuraux sous-tendant la perturbation du comportement de cour suite à l'exposition adulte au di- (2-éthylexyl) phtalate chez la souris

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Adult male mice exposure to nonylphenol alters courtship vocalizations and mating

International audienceThe neural circuitry processing male sexual behavior is tightly regulated by testosterone and its neural metabolite estradiol. The present study evaluated the effects of adult exposure to low doses of nonylphenol (NP), a widespread environmental contaminant, on the neuroendocrine regulation of testosterone and expression of sexual behavior. Oral exposure of C57BL/6J males to NP (0.5, 5 or 50 μg/kg/day) for 4 weeks did not affect circulating levels of testosterone or the kisspeptin system, a key regulator of the gonadotropic axis. In contrast, mice exposed to NP at 5 μg/kg/day emitted an increased number and duration of ultrasonic vocalizations, took longer to reach ejaculation and showed increased number of mounts, intromissions and thrusts. This was associated with normal olfactory preference and locomotor activity, and increased anxiety level. Analysis of the neural circuitry that underlies sexual behavior showed changes in the number of cells expressing androgen and estrogen receptors in males exposed to NP at 5 μg/kg/day. The neural circuitry underlying sexual behavior is thus highly sensitive to adult exposure to NP. Furthermore, almost all the observed effects were induced at 5 μg/kg/day of NP, indicating that this endocrine disrupter triggers a non-monotonic response in the adult male mouse brain

Neural Androgen Receptor Deletion Impairs the Temporal Processing of Objects and Hippocampal CA1-Dependent Mechanisms

International audienceWe studied the role of testosterone, mediated by the androgen receptor (AR), in modulating temporal order memory for visual objects. For this purpose, we used male mice lacking AR specifically in the nervous system. Control and mutant males were gonadectomized at adulthood and supplemented with equivalent amounts of testosterone in order to normalize their hormonal levels. We found that neural AR deletion selectively impaired the processing of temporal information for visual objects, without affecting classical object recognition or anxiety-like behavior and circulating corticosterone levels, which remained similar to those in control males. Thus, mutant males were unable to discriminate between the most recently seen object and previously seen objects, whereas their control littermates showed more interest in exploring previously seen objects. Because the hippocampal CA1 area has been associated with temporal memory for visual objects, we investigated whether neural AR deletion altered the functionality of this region. Electrophysiological analysis showed that neural AR deletion affected basal glutamate synaptic transmission and decreased the magnitude of N-methyl-D-aspartate receptor (NMDAR) activation and high-frequency stimulation induced long-term potentiation. The impairment of NMDAR function was not due to changes in protein levels of receptor. These results provide the first evidence for the modulation of temporal processing of information for visual objects by androgens, via AR activation , possibly through regulation of NMDAR signaling in the CA1 area in male mice

Systems genetic analysis of osteoblast-lineage cells

The osteoblast-lineage consists of cells at various stages of maturation that are essential for skeletal development, growth, and maintenance. Over the past decade, many of the signaling cascades that regulate this lineage have been elucidated; however, little is known of the networks that coordinate, modulate, and transmit these signals. Here, we identify a gene network specific to the osteoblast-lineage through the reconstruction of a bone co-expression network using microarray profiles collected on 96 Hybrid Mouse Diversity Panel (HMDP) inbred strains. Of the 21 modules that comprised the bone network, module 9 (M9) contained genes that were highly correlated with prototypical osteoblast maker genes and were more highly expressed in osteoblasts relative to other bone cells. In addition, the M9 contained many of the key genes that define the osteoblast-lineage, which together suggested that it was specific to this lineage. To use the M9 to identify novel osteoblast genes and highlight its biological relevance, we knocked-down the expression of its two most connected "hub" genes, Maged1 and Pard6g. Their perturbation altered both osteoblast proliferation and differentiation. Furthermore, we demonstrated the mice deficient in Maged1 had decreased bone mineral density (BMD). It was also discovered that a local expression quantitative trait locus (eQTL) regulating the Wnt signaling antagonist Sfrp1 was a key driver of the M9. We also show that the M9 is associated with BMD in the HMDP and is enriched for genes implicated in the regulation of human BMD through genome-wide association studies. In conclusion, we have identified a physiologically relevant gene network and used it to discover novel genes and regulatory mechanisms involved in the function of osteoblast-lineage cells. Our results highlight the power of harnessing natural genetic variation to generate co-expression networks that can be used to gain insight into the function of specific cell-types