Cell of origin dictates aggression and stem cell activity in acute lymphoblastic leukemia
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ABSTRACT:
PROVIDER: PRJNA428951 | ENA |
REPOSITORIES: ENA
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Project description:Subclassification of lymphoid neoplasms is often based on the presumed cell of origin based on T and B progenitor gene expression and the effect of cell lineage on influencing functional characteristics such as aggression and self-renewal capacity is largely unknown, accounted for in part, by lack of experimental models to address these questions. Here, we have used transgenic zebrafish to create the first models of Myc-induced B-ALL and mixed phenotypic B/T-ALL, opening new avenues for studying the these leukemias in the zebrafish. Our work has utilized syngeneic strain zebrafish, limiting dilution cell transplantation, and the widely reported rag2-Myc transgenic model to provide new understanding of how strain differences can underlie leukemia onset in the zebrafish model. Even more importantly, our work now for the first time, has allowed assessment of cell lineage on dictating aggression and leukemia stem cell frequency independent of the underlying oncogenic driver. In total, our work uncoveres that T-ALLs are more aggressive and have higher numbers of leukemia stem cells when compared with B-ALL and mixed phenotypic ALL. Furthermore, analysis of our biphenotypic B/T-ALL suggests that B cell pathways lock cells in less aggressive and lower stem cell fates and are dominant in regulating these processes when T cell pathways are co-regulated within ALL cells.
2018-04-29 | GSE108855 | GEO
Project description:Cell of Origin of Malignant Mesothelioma dictates the tumor subtype
| PRJNA515490 | ENA
Project description:Malignant Mesothelioma (MM) is one of the most lethal human malignancies of the thoracic cavity. We have determined the cell of origin of these tumors by inactivating Nf2 and Trp53 in Cdkn2a-deficient mesothelial cells both in vitro and in vivo. Cloned, in vitro switched cell lines showed distinct protein marker profiles that upon grafting in recipient mice, gave rise to epithelial, sarcomatoid or biphasic MM. We show that corresponding cell types are present in the mesothelial lining, each capable to serve as a cell of origin of one of the distinct MM subtypes of which the RNA expression profile aligns with corresponding human samples. Therefore, the specific target cell is a critical factor in dictating the tumor subtype of MM.
2021-01-13 | GSE125185 | GEO
Project description:Modulation of action choices according to the environmental context is crucial for animal survival and reproductive success1. Aggression, despite its general importance as a social behavior2, can become detrimental if uncontrolled3,4. However, the genetic and neural basis for aggression control through active suppression remains largely unknown. Here we found nvy, a Drosophila homolog of vertebrate myeloid translocation gene (MTG)5 involved in transcriptional regulation6-8, suppresses aggression through a specific subset of neurons. Mutation of the nvy gene resulted in hyper-aggressiveness, which was rescued by neuronal expression of human MTGs as well as Drosophila nvy. The mutant exhibited persistent aggression under various contexts in which wild-type flies switch their behavioral patterns. Knockdown of nvy in octopaminergic/tyraminergic (OA/TA) neurons increased aggression, phenocopying the nvy deletion. Cell-type specific transcriptomics on OA/TA neurons derived from the nvy mutants revealed aggression-controlling genes that are likely downstream of nvy. Moreover, we found that the nvy-expressing OA/TA neuronal subpopulations specifically suppress aggression. Our results presents a powerful genetic model to unravel not only the neuronal systems that modulate aggression in a social context-dependent manner, but also the conserved molecular mechanism underlying the tumorigenesis caused by the MTG mutations.
2022-06-22 | GSE148630 | GEO
Project description:High frequency of physical aggression is the central feature of severe conduct disorder and is associated with a wide range of social, mental and physical health problems. We have previously tested the hypothesis that differential DNA methylation signatures in peripheral T cells are associated with a chronic aggression trajectory in males. Despite the fact that sex differences appear to play a pivotal role in determining the development, magnitude and frequency of aggression, most of previous studies focused on males, so little is known about female chronic physical aggression. We therefore tested here whether or not there is a signature of physical aggression in female DNA methylation and, if there is, how it relates to the signature observed in males. Genome-wide promoter methylation profiles of T cell DNA from adult females on a Chronic Physical Aggression (CPA, n=5) trajectory during childhood and adolescence were compared to those on normative physical aggression trajectories (NPA, n=14). Two technical replicates were generated for each individual.
2013-12-11 | E-GEOD-53192 | biostudies-arrayexpress
Project description:Genes relevant to manifestion of and variation in aggression behavior might be differentially expressed in lines selected for divergent levels of aggression. Keywords: selection group
2006-08-30 | GSE5404 | GEO
Project description:In this study, we set out to get insight into the clinical implications of FADD expres-sion in T-cell lymphoblastic neoplasms, and to explore the landscape of deregulated cell signaling events in human T-cell lymphoblastic neoplasms, taking FADD expression as the defining variable.
2023-03-11 | PXD037858 | Pride
Project description:High frequency of physical aggression is the central feature of severe conduct disorder and is associated with a wide range of social, mental and physical health problems. We have previously tested the hypothesis that differential DNA methylation signatures in peripheral T cells are associated with a chronic aggression trajectory in males. Despite the fact that sex differences appear to play a pivotal role in determining the development, magnitude and frequency of aggression, most of previous studies focused on males, so little is known about female chronic physical aggression. We therefore tested here whether or not there is a signature of physical aggression in female DNA methylation and, if there is, how it relates to the signature observed in males. Genome-wide promoter methylation profiles of T cell DNA from adult males and females on a Chronic Physical Aggression (CPA) trajectory during childhood and adolescence were compared to adults on a normative physical aggression trajectories (NPA). Each sample was bisulphite converted gDNA pooled in equimolar amounts. Three different pools of genomic DNA were made per group: male CPA (2 or 3 different subjects per pool), male NPA (4 different subjects per pool), female CPA (2 different subjects per pool) and female NPA (4 or 5 different subjects per pool) . The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles of the 2 groups in both sex.
2013-12-11 | E-GEOD-53191 | biostudies-arrayexpress
Project description:Chronic physical aggression (CPA) is characterized by frequent use of physical aggression from early childhood to adolescence. Observed in approximately 5% of males, it is associated with early childhood adverse environments. DNA methylation, a covalent modification of DNA, regulates genome function and has been associated with early childhood adverse environments. We analyzed T cell DNA genome-wide promoter methylation profiles from two groups of adult males assessed annually for frequency of physical aggression between 6 and 15 years of age: a group with CPA and a control group. Whole genome methylation analysis was performed using MeDIP followed by hybridization to microarrays. We mapped the promoter regions of 20 000 genes and 400 microRNAs. The subjects were recruited from participants in two longitudinal studies of child development9,47. We recruited two groups of Caucasian males who were born in families with a low socioeconomic status and were living at the time of the present study within 200km from our laboratory. The first group had a history of high physical aggression from age 6 to 15 years (chronic physical aggression group, CPA). The second group was recruited from the same longitudinal studies but included only those who did not have a history of high physical aggression from age 6 to 15 (Control group). A total of 65 eligible subjects agreed to participate (8 CPA and 57 controls). Using custom-designed microarrays with 244K probes tiling the promoter regions of 20000 genes and 400 microRNAs, we obtained DNA methylation profiles by meDIP-chip. Each profile was generated in triplicate.
2013-09-30 | E-GEOD-50674 | biostudies-arrayexpress
Project description:Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1a, IL-4, IL-6, IL-8 and IL-10, later in early adulthood (Provencal et al., unpublished data). This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. We compared the methylation profiles of the entire genomic loci encompassing the IL-1a, IL-6, IL-4, IL10 and IL8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group). We used the method of methylated DNA immunoprecipitation (MeDIP) with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We recruited two groups of Caucasian males who were born in families with a low socioeconomic status and were living at the time of the present study within 200km from our laboratory. The first group, composed of 8 subjects, had a history of chronic physical aggression from age 6 to 15 years (chronic physical aggression group, CPA). The second group, composed of 12 subjects, was recruited from the same longitudinal studies but included only those who did not have a history of chronic physical aggression from age 6 to 15 (Control group, CG). Using custom-designed microarrays with 44K probes tiling cytokines IL-1a, IL-6, IL-4, IL10 and IL8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6, we obtained DNA methylation profiles by meDIP-chip. Each profile was generated in triplicate.
2013-05-22 | E-GEOD-47193 | biostudies-arrayexpress