Cannabinoid receptor gene CNR1 is downregulated in subcortical brain samples and upregulated in blood samples of individuals with schizophrenia: A participant data systematic meta-analysis.

Cannabis use leads to symptom exacerbation in schizophrenia patients, and endocannabinoid ligands have been studied as tentative schizophrenia therapeutics. Here, we aimed to characterise the connection between schizophrenia and the cannabinoid receptor 1 gene (CNR1) and explore possible mechanisms affecting its expression in schizophrenia. We performed a participant data systematic meta-analysis of CNR1 gene expression and additional endocannabinoid system genes in both brain (subcortical areas) and blood samples. We integrated eight brain sample datasets (overall 316 samples; 149 schizophrenia and 167 controls) and two blood sample datasets (overall 90 samples; 53 schizophrenia and 37 controls) while following the PRISMA meta-analysis guidelines. CNR1 was downregulated in subcortical regions and upregulated in blood samples of patients with schizophrenia. CNR2 and genes encoding endocannabinoids synthesis and degradation did not show differential expression in the brain or blood, except fatty acid amide hydrolase (FAAH), which showed a downregulation trend in blood. In addition, the brain expression levels of CNR1 and three GABA receptor genes, GABRA1, GABRA6 and GABRG2, were positively correlated (R = .57, .36, .54; p = 2.7 × 10-14 , 6.9 × 10-6 and 1.1 × 10-12 , respectively). Brain CNR1 downregulation and the positive correlation with three GABA receptor genes suggest an association with GABA neurotransmission and possible effects on negative schizophrenia symptoms. Further studies are required for clarifying the opposite CNR1 dysregulation in the brain and blood of schizophrenia patients and the potential of endocannabinoid ligands as schizophrenia therapeutics.

Ribosome subunits are upregulated in brain samples of a subgroup of individuals with schizophrenia: A systematic gene expression meta-analysis.

One of the new theories accounting for the underlying pathophysiology of schizophrenia is excitation/inhibition imbalance. Interestingly, perturbation in protein synthesis machinery as well as oxidative stress can lead to excitation/inhibition imbalance. We thus performed a systematic meta-analysis of the expression of 79 ribosome subunit genes and two oxidative-stress related genes, HIF1A and NQO1, in brain samples of individuals with schizophrenia vs. healthy controls. We integrated 12 gene expression datasets, following the PRISMA guidelines (overall 511 samples, 253 schizophrenia and 258 controls). Five ribosome subunit genes were significantly upregulated in a subgroup of the patients with schizophrenia, while 24 (30%) showed a tendency for upregulation. HIF1A and NQO1 were also found to be significantly upregulated. Moreover, HIF1A and NQO1 showed positive correlation with the expression of the upregulated ribosome subunit genes. Our results, together with previous findings, suggest a possible role for altered mRNA translation in the pathogenesis of schizophrenia, in association with markers of increased oxidative stress in a subgroup of patients. Further studies should define whether the upregulation of ribosome subunits result in altered mRNA translation, which proteins are modulated and how it characterizes a subgroup of the patients with schizophrenia.

Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia.

OBJECTIVES: Schizophrenia is a chronic, debilitating mental disorder whose pathophysiology is complex and not fully understood. Numerous studies suggest mitochondrial dysfunction may contribute to the development of schizophrenia. While mitochondrial ribosomes (mitoribosomes) are essential for proper mitochondrial functioning, their gene expression levels have not been studied yet in schizophrenia. METHODS: We performed a systematic meta-analysis of the expression of 81 mitoribosomes subunits encoding genes, integrating ten brain samples datasets of patients with schizophrenia compared to healthy controls (overall 422 samples, 211 schizophrenia, and 211 controls). We also performed a meta-analysis of their expression in blood, integrating two blood sample datasets (overall 90 samples, 53 schizophrenia, and 37 controls). RESULTS: Multiple mitoribosomes subunits were significantly downregulated in brain samples (18 genes) and in blood samples (11 genes) of individuals with schizophrenia, where two showed significant downregulation in both brain and blood, MRPL4 and MRPS7. CONCLUSIONS: Our results support the accumulating evidence of impaired mitochondrial activity in schizophrenia. While further research is needed to validate mitoribosomes' role as biomarkers, this direction has the potential to promote patients' stratification and personalised treatment for schizophrenia.

Up-Regulation of S100 Gene Family in Brain Samples of a Subgroup of Individuals with Schizophrenia: Meta-analysis.

The S100 proteins family is known to affect neuroinflammation and astrocyte activation, which have been suggested to be contributors to the pathogenesis of schizophrenia. We conducted a systematic meta-analysis of S100 genes differential expression in postmortem samples of patients with schizophrenia vs. healthy controls, following the commonly used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Twelve microarray datasets met the inclusion criteria (overall 511 samples, 253 schizophrenia and 258 controls were analyzed). Nine out of 21 genes were significantly up-regulated or with tendency for up-regulation. A per-sample fold change analysis indicated that the S100 genes' up-regulation was concentrated in a subgroup of the patients. None of the genes have been found to be down-regulated. ANXA3, which encodes Annexin 3 protein and was associated with neuroinflammation, was up-regulated and positively correlated with the S100 genes' expression pattern. In addition, astrocytes and endothelial cell markers were significantly correlated with S100A8 expression. S100 correlation with ANXA3 and endothelial cell markers suggests that the up-regulation we detected reflects increased inflammation. However, it might also reflect astrocytes abundance or activation. The fact that S100 proteins were shown to be up-regulated in blood samples and other body fluids of patients with schizophrenia suggests a potential role as biomarkers, which might help disease subtyping, and the development of etiological treatments for immune dysregulation in schizophrenia.

SMAD genes are up-regulated in brain and blood samples of individuals with schizophrenia.

Schizophrenia is a severe psychiatric disorder, with heritability around 80%, but a not fully understood pathophysiology. Signal transduction through the mothers against decapentaplegic (SMADs) are eight different proteins involved in the regulation of inflammatory processes, cell cycle, and tissue patterning. The literature is not consistent regarding the differential expression of SMAD genes among subjects with schizophrenia. In this article, we performed a systematic meta-analysis of the expression of SMAD genes in 423 brain samples (211 schizophrenia vs. 212 healthy controls), integrating 10 datasets from two public repositories, following the PRISMA guidelines. We found a statistically significant up-regulation of SMAD1, SMAD4, SMAD5, and SMAD7, and a tendency for up-regulation of SMAD3 and SMAD9 in brain samples of patients with schizophrenia. Overall, six of the eight genes showed a tendency for up-regulation, and none of them was found to have a tendency for down-regulation. SMAD1 and SMAD4 were up-regulated also in blood samples of 13 individuals with schizophrenia versus eight healthy controls, suggesting the SMAD genes' potential role as biomarkers of schizophrenia. Furthermore, SMAD genes' expression levels were significantly correlated with those of Sphingosine-1-phosphate receptor-1 (S1PR1), which is known to regulate inflammatory processes. Our meta-analysis supports the involvement of SMAD genes in the pathophysiology of schizophrenia through their role in inflammatory processes, as well as demonstrates the importance of gene expression meta-analysis for improving our understanding of psychiatric diseases.

Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males.

Schizophrenia is a chronic and debilitating mental disorder, with unknown pathophysiology. Converging lines of evidence suggest that mitochondrial functioning may be compromised in schizophrenia. Postmortem brain samples of individuals with schizophrenia showed dysregulated expression levels of genes encoding enzyme complexes comprising the mitochondrial electron transport chain (ETC), including ATP synthase, the fifth ETC complex. However, there are inconsistencies regarding the direction of change, i.e., up- or down-regulation, and differences between female and male patients were hardly examined. We have performed a systematic meta-analysis of the expression of 16 ATP synthase encoding genes in postmortem brain samples of individuals with schizophrenia vs. healthy controls of three regions: Brodmann Area 10 (BA10), BA22/Superior Temporal Gyrus (STG) and the cerebellum. Eight independent datasets were integrated (overall 294brain samples, 145 of individuals with schizophrenia and 149 controls). The meta-analysis was applied to all individuals with schizophrenia vs. the controls, and also to female and male patients vs. age-matched controls, separately. A significant down-regulation of two ATP synthase encoding genes was detected in schizophrenia, ATP5A1 and ATP5H, and a trend towards down-regulation of five further ATP synthase genes. The down-regulation tendency was shown for both females and males with schizophrenia. Our findings support the hypothesis that schizophrenia is associated with reduced ATP synthesis via the oxidative phosphorylation system, which is caused by reduced cellular demand of ATP. Abnormal cellular energy metabolism can lead to alterations in neural function and brain circuitry, and thereby to the cognitive and behavioral aberrations characteristic of schizophrenia.

VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis.

Mitochondrial dysfunction was shown to be involved in schizophrenia pathophysiology. Abnormal energy states can lead to alterations in neural function and thereby to the cognitive and behavioral aberrations characteristics of schizophrenia. Voltage-dependent anion-selective channels (VDAC) are located in the outer mitochondrial membrane and are involved in mitochondrial energy production. Only few studies explored VDAC genes' expression in schizophrenia, and their results were not consistent. We conducted a systematic meta-analysis of ten brain samples gene expression datasets (overall 368 samples, 179 schizophrenia, 189 controls). In addition, we conducted a meta-analysis of three blood samples datasets (overall 300 samples, 167 schizophrenia, 133 controls). Pairwise correlation analysis was conducted between the VDAC and proteasome subunit genes' expression patterns. VDAC1, VDAC2 and VDAC3 showed significant down-regulation in brain samples of patients with schizophrenia. They also showed significant positive correlations with the proteasome subunit genes' expression levels. Our findings suggest that VDAC genes might play a role in mitochondrial dysfunction in schizophrenia. VDAC1 was down-regulated also in blood samples, which suggests its potential role as a biomarker for schizophrenia. The correlation with proteasome subunits, which were previously shown to be down-regulated in a subgroup of the patients, suggests that our findings might characterize a subgroup of the patients. This direction has the potential to lead to patients' stratification and more precisely-targeted therapy and necessitates further study.

Gene expression meta-analysis in patients with schizophrenia reveals up-regulation of RGS2 and RGS16 in Brodmann Area 10.

Regulator of G-protein signalling (RGS) proteins inhibit signalling by G-protein-coupled receptors (GPCRs). GPCRs mediate the functions of several important neurotransmitters and serve as targets of many anti-psychotics. RGS2, RGS4, RGS5 and RGS16 are located on chromosome 1q23.3-31, a locus found to be associated with schizophrenia. Although previous gene expression analysis detected down-regulation of RGS4 expression in brain samples of patients with schizophrenia, the results were not consistent. In the present study, we performed a systematic meta-analysis of differential RGS2, RGS4, RGS5 and RGS16 expression in Brodmann Area 10 (BA10) samples of patients with schizophrenia and from healthy controls. Two microarray datasets met the inclusion criteria (overall, 41 schizophrenia samples and 38 controls were analysed). RGS2 and RGS16 were found to be up-regulated in BA10 samples of individuals with schizophrenia, whereas no differential expression of RGS4 and RGS5 was detected. Analysis of dorso-lateral prefrontal cortex samples of the CommonMind Consortium (258 schizophrenia samples vs. 279 controls) further validated the results. Given their central role in inactivating G-protein-coupled signalling pathways, our results suggest that differential gene expression might lead to enhanced inactivation of G-protein signalling in schizophrenia. This, in turn, suggests that additional studies are needed to further explore the consequences of the differential expression we detected, this time at the protein and functional levels.

Buffering effect of in-patient psychiatric care on the link between fear of covid-19 and mental health consequences.

BACKGROUND& AIMES: Psychiatric admissions during the covid-19 pandemic were limited, overlooking their possible benefit. This study focused on assessing the effect of the fear of covid on the mental health and well-being of inpatients as opposed to outpatients. METHODS: During the first lockdown, forty-four inpatients and day care patients (inpatient group) and 74 outpatients (outpatient group) were recruited after an informed consent procedure. Fear of the infection was assessed using the Fear of COVID-19 (FCV-19S); severity of mental health symptomatology was evaluated with the outcome questionnaire-45 (OQ-45); wellbeing was assessed with the Psychological well-being scale (PWB). OUTCOMES: There was no difference between the inpatient group and outpatient group in their fear of COVID-19 levels.FCV-19 predicted changes in the outpatient OQ total score (B â€‹= â€‹2.21, p â€‹< 0.001), OQ interpersonal relation subscale (B â€‹= â€‹0.34, p â€‹= 0.01), PWB total score (B â€‹= â€‹-0.05, p â€‹< 0.001), PWB environmental mastery subscale (B â€‹= â€‹-0.07, p â€‹< 0.001) and PWB positive relation subscale (B â€‹= â€‹-0.05, p â€‹< 0.001), but not in the inpatient group. CONCLUSIONS: Mental health and wellbeing of the outpatient group, which had less therapeutic contact than the inpatient group, correlated with the fear of covid, supporting the hypothesis that intensive psychiatric therapy had a protective effect on the mental health consequences of "fear of covid".

Attitudes of patients with severe mental illness towards COVID-19 vaccinations: A preliminary report from a public psychiatric hospital.

BACKGROUND: As patients with severe mental illness are at increased risk for COVID-19 mortality, the issue of willingness to be vaccinated is of extreme importance. METHODS: During February 2021 Shalvata Mental Health hospital provided Covid-19 vaccines to its patients. Fifty one patients suffering from severe mental illness, out of 196 patients hospitalized in closed, open or day wards during that period, signed the informed consent and were assessed for their clinical condition (OQ-45), fear of Covid-19 (FCV-19S) and approach to the vaccine (C19-VHS). All patients who were not vaccinated in February 2021 (baseline) were re-approached a month later to assess whether they had gotten vaccinated since. RESULTS: Patients who were not vaccinated at baseline had an oppositional approach to the vaccine, and did not significantly differ in their fear of Covid-19 levels or in levels of clinical severity (t(49) = 2.51, p = 0.02) from those who were vaccinated. From the 29 patients who were not vaccinated at baseline approach to the vaccine was a good predictor to getting vaccinated after one month (79% positive predictive value). CONCLUSIONS: The majority of patients suffering from a severe mental illness are willing to get vaccinated, and their decision of whether or not to get vaccinated is based on their viewpoint on the vaccine rather than being an outcome of their level of distress (OQ-45). It is important to allow vaccine accessibility to hospitalized patients, to consider their opinions and to provide useful information to lower vaccine hesitancy and improve vaccination rates.

Blood transcriptional response to treatment-resistant depression during electroconvulsive therapy.

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment. This study aimed to elucidate the transcriptional differences in peripheral blood mononuclear cells (PBMC) between individuals with TRD and a control group without a psychiatric illness; and between patients with TRD, treated with either standard antidepressant drugs alone, or in combination with ECT or ketamine. Additionally, PBMC transcriptomics were compared between treatment responders, following completion of their treatment protocols. Total RNA was extracted from PBMC of the TRD group at two time points, and RNA and miRNA expression were profiled. Multiple mRNAs and miRNAs were found to be modified, with two protein coding genes, FKBP5 and ITGA2B, which are up- and downregulated, respectively; and several miRNAs have shown changes following successful ECT treatment. Further analysis demonstrated the direct functional regulation of ITGA2B by miR-24-3p. Our findings suggest that PBMC expression levels of FKBP5, ITGA2B, and miR-24-3p should be further explored as tentative ECT response biomarkers.

Gene Expression Meta-Analysis of Cerebellum Samples Supports the FKBP5 Gene-Environment Interaction Model for Schizophrenia.

BACKGROUND: One of the most studied molecular models of gene-environment interactions is that of FKBP5, which has been shown to interact with childhood adversity to increase the risk of psychiatric disorders, and has been implicated in schizophrenia. While the model predicts up-regulation of FKBP5, previous brain samples gene expression studies yielded inconsistent results. METHODS: We performed a systematic gene expression meta-analysis of FKBP5 and NR3C1, a glucocorticoid receptor inhibited by FKBP5, in cerebellum samples of patients with schizophrenia. The gene expression databases GEO, SMRI and those of NIMH were searched, and out of six screened datasets, three were eligible for the meta-analysis (overall 69 with schizophrenia and 78 controls). RESULTS: We detected up-regulation of FKBP5 and down-regulation of NR3C1 in schizophrenia, and a negative correlation between their expression patterns. Correlation analysis suggested that the detected differential expression did not result from potential confounding factors. CONCLUSIONS: Our results give significant support to the FKBP5 gene-environment interaction model for schizophrenia, which provides a molecular mechanism by which childhood adversity is involved in the development of the disorder. To explore FKBP5's potential as a therapeutic target, a mapping of its differential expression patterns in different brain regions of schizophrenia patients is needed.

Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia.

BACKGROUND: The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients. METHODS: Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets. RESULTS: The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia. CONCLUSIONS: We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

Gene expression meta-analysis reveals the up-regulation of CREB1 and CREBBP in Brodmann Area 10 of patients with schizophrenia.

Cognitive impairments characterize individuals with schizophrenia, and are correlated to the patients' functional outcome. The transcription factor Cyclic AMP-responsive element-binding protein-1 (CREB1) is involved in learning and memory processes. CREB1 and both CREB-binding protein (CREBBP) and E1A Binding Protein P300 (EP300), co-activators of CREB1, have been associated with schizophrenia. We performed a systematic meta-analysis of CREB1, CREBBP and EP300 differential expression in post mortem Brodmann Area 10 (BA10) samples of patients with schizophrenia vs. healthy controls, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Two microarray datasets met the inclusion criteria (overall 41 schizophrenia samples and 38 controls were analyzed). We detect up-regulation of CREB1 and CREBBP in BA10 samples of patients with schizophrenia, while EP300 wasn't differentially expressed. The integration of two independent datasets and the positive correlation between the expression patterns of CREB1 and CREBBP increase the validity of the results. The up-regulation of CREB1 and its co-activator CREBBP might relate to BA10 altered activation that has been shown in schizophrenia. As BA10 was shown to be involved in the cognitive impairments associated with schizophrenia, this suggests involvement of CREB1 and CREBBP in the cognitive symptoms that characterize the disease.

Gene expression meta-analysis reveals the down-regulation of three GABA receptor subunits in the superior temporal gyrus of patients with schizophrenia.

One of the main theories accounting for the underlying pathophysiology of schizophrenia posits alterations in GABAergic neurotransmission. While previous gene expression studies of postmortem brain samples typically report the down-regulation of GABA related genes in schizophrenia, the results are often inconsistent and not uniform across studies. We performed a systematic gene expression analysis of 22 GABA related genes in postmortem superior temporal gyrus (STG) samples of 19 elderly subjects with schizophrenia (mean age: 77) and 14 matched controls from the Icahn school of Medicine at Mount Sinai (MSSM) cohort. To test the validity and robustness of the resulting differentially expressed genes, we then conducted a meta-analysis of the MSSM and an independent dataset from the Stanley Consortium of 14 STG samples of relatively young subjects with schizophrenia (mean age: 44) and 15 matched controls. For the first time, the findings showed the down-regulation of three GABA-receptor subunits of type A, GABRA1, GABRA2 and GABRB3, in the STG samples of subjects with schizophrenia, in both the elderly and the relatively young patients. These findings, as well as previous results, lend weight to the notion of a common upstream pathology that alters GABAergic neurotransmission in schizophrenia. GABRA1, GABRA2 and GABRB3 down-regulation may contribute to the pathophysiology and clinical manifestations of schizophrenia through altered oscillation synchronization in the STG.

Individual Psychotherapy ("Talking Therapy"): A Survey of Attitudes among Residents & Specialists in Psychiatry, Israel 2010-2011.

BACKGROUND: Individual psychotherapy is an efficient tool and an integral part of psychiatric treatment. However, its status among psychiatrists in Israel has never been explored. OBJECTIVES: To explore and map the attitudes of psychiatrists in Israel regarding psychotherapy and psychotherapy training during residency, with comparisons between residents vs. specialists, peripheral vs. central institutions and mental health vs. medical centers. METHOD: We conducted a cross-sectional survey to examine the attitudes toward individual psychotherapy. The questionnaire was delivered via email and direct approach to psychiatrists in Israel. RESULTS: The survey was completed by 229 of 1,502 registered psychiatrists (15.3%). While 96% (n=218) had positive attitudes towards psychotherapy, 93.1% (n=215) thought psychotherapy was less available than pharmacotherapy. Psychiatrists from peripheral institutions prefer cognitive behavioral therapy, while psychiatrists from central institutions prefer dynamic psychotherapy. Psychiatrists from mental health centers use more dynamic psychotherapy compared to psychiatrists from medical centers. The number of dynamic psychotherapy treatments psychiatrists delivered during their residencies has been decreasing over time, meaning residents today deliver fewer dynamic psychotherapy treatments compared to the number of treatments specialists delivered during their residencies. Additionally, 97.4% (n=225) believed psychotherapy training should be included in the psychiatric residency and 87.3% thought that the training should be improved to a great extent. CONCLUSIONS: The survey demonstrates mixed but overall positive attitudes towards psychotherapy among psychiatrists in Israel. The findings should be taken into consideration by psychiatrists who design the residency program and by policy makers who are in charge of the mental health reform in Israel, or the psychotherapy usage and therapeutic potential may diminish, as has happened in other countries.

Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment.

Social behaviour has a key role in animal survival across species, ranging from insects to primates and humans. However, the biological mechanisms driving natural interactions between multiple animals, over long-term periods, are poorly studied and remain elusive. Rigorous and objective quantification of behavioural parameters within a group poses a major challenge as it requires simultaneous monitoring of the positions of several individuals and comprehensive consideration of many complex factors. Automatic tracking and phenotyping of interacting animals could thus overcome the limitations of manual tracking methods. Here we report a broadly applicable system that automatically tracks the locations of multiple, uniquely identified animals, such as mice, within a semi-natural setting. The system combines video and radio frequency identified tracking data to obtain detailed behavioural profiles of both individuals and groups. We demonstrate the usefulness of these data in characterizing individual phenotypes, interactions between pairs and the collective social organization of groups.

Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.

We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways.