Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation.

Pediatric acute myeloid leukemia frequently harbors fusion oncogenes associated with poor prognosis, including KMT2A, NUP98, and GLIS2 rearrangements. Although murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in the ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSCs).

CD36 cell surface expression as a surrogate marker to identify ABL/JAK-class kinase fusions in pediatric BCP-ALL.

Genetic alterations are the cornerstone of risk stratification in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and their accurate identification is critical for optimal treatment. Most cases with ABL-class fusion are classified as high-risk yet display good responses to tyrosine kinase inhibitors (TKIs). Current clinical protocols recommend adding a TKI to chemotherapy as soon as possible, making it mandatory to rapidly identify these alterations.

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.

Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes.

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death.

Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model.

Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/-, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations.

De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells.

Background: Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion.

Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers.

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden.

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as , are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed leukemogenic potential.

Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis.

Background: Negative symptoms are among the most chronic symptoms of schizophrenia. Even with the advent of atypical antipsychotic drugs, negative symptoms remain mostly refractory to treatment. It has been proposed that selective serotonin reuptake inhibitor (SSRI) augmentation therapy in schizophrenia could provide a greater relief of these symptoms.

Quetiapine augmentation of treatment-resistant depression: a comparison with lithium.

Objective: The prevalence of and morbidity associated with treatment-resistant depression has motivated the exploration of treatment alternatives. In this study, quetiapine was compared with lithium in the augmentation of treatment-resistant depression.

Research Design And Methods: Open-label, comparative study in 20 patients with major depression who had failed to respond after 4 weeks of treatment with an antidepressant at the maximal recommended dose.

Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial.

Background: Preliminary evidence suggests that clozapine relieves the craving for psychoactive substances in schizophrenia patients. Quetiapine shares crucial pharmacological properties with clozapine. Promising results have been described with quetiapine therapy in patients with psychosis and substance use disorder.

Impact of a unilateral brain lesion on cortisol secretion and emotional state: anterior/posterior dissociation in humans.

The main goal of this study was to evaluate whether a unilateral brain lesion in a human population is associated with a modification of the circadian cortisol secretion profile, and/or patient's emotional state. The second goal of this study was to assess whether there would be differences in both the pattern of cortisol secretion and emotional state in brain-damaged patients as a function of side of lesion, and localization (anterior vs posterior) of lesion. Eight patients with a left cortical lesion, six patients with a right cortical lesion, four patients with basal ganglia lesions (2 left and 2 right) and ten healthy volunteers were evaluated daily on measures of salivary cortisol levels and subjective feelings of joy and sadness at 0700, 1200, 1600 and 1900 hours over a 15-day period.

Strategies of collaboration between general practitioners and psychiatrists: a survey of practitioners' opinions and characteristics.

Background: The description of collaboration models and the key underlying principles provide important information for designing services. However, to apply this broad corpus of information to clinical services and policymaking, we need to know which key principles (or strategies) of collaboration are the most accepted by local physicians.

Method: In this context, we designed a survey that included 2 objectives: 1) to collect the opinions of practising general practitioners (GPs) and psychiatrists in Montreal with respect to strategies for improving collaboration between these 2 groups and 2) to identify demographic and practice characteristics of those physicians associated with the acceptance of such strategies.