CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in ALL.

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes.

Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia.

Background: Alterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias.

Methods: A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed.

Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion.

Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials.

Distinct transcriptomic profile of small arteries of hypertensive patients with chronic kidney disease identified miR-338-3p targeting GPX3 and PTPRS.

Objective: Hypertension is associated with vascular injury, which contributes to end-organ damage. MicroRNAs regulating mRNAs have been shown to play a role in vascular injury in hypertensive mice. We aimed to identify differentially expressed microRNAs and their mRNA targets in small arteries of hypertensive patients with/without chronic kidney disease (CKD) to shed light on the pathophysiological molecular mechanisms of vascular remodeling.

Identification of new ETV6 modulators through a high-throughput functional screening.

transcriptional activity is critical for proper blood cell development in the bone marrow. Despite the accumulating body of evidence linking malfunction to hematological malignancies, its regulatory network remains unclear. To uncover genes that modulate repressive transcriptional activity, we performed a specifically designed, unbiased genome-wide shRNA screen in pre-B acute lymphoblastic leukemia cells.

Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells.

Purpose: Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging.

Role of rs10406069 in miR-5196 in hyperdiploid childhood acute lymphoblastic leukemia.

To determine the role of single nucleotide polymorphisms (SNPs) in noncoding RNAs in childhood acute lymphoblastic leukemia (ALL) subtypes. We screened all SNPs in 130 pre-miRNA genes to assess their role in the susceptibility of the most common subtypes of ALL: hyperdiploid and . In two independent cohorts, we found a significant association between rs10406069 in miR-5196 and the risk of developing hyperdiploid ALL.

Chromosome 2 Fragment Substitutions in Dahl Salt-Sensitive Rats and RNA Sequencing Identified and as Vascular Inflammatory Modulators.

Chromosome 2 introgression from normotensive Brown Norway (BN) rats into hypertensive Dahl salt-sensitive (SS) background (SS-chromosome 2/Mcwi; consomic S2) reduced blood pressure and vascular inflammation under a normal-salt diet (NSD). We hypothesized that BN chromosome 2 contains anti-inflammatory genes that could reduce blood pressure and vascular inflammation in rats fed NSD or high-salt diet (HSD). Four- to 6-week old male SS and congenic rats containing the BN chromosome 2 distal portion (SS.

Single-cell analysis of childhood leukemia reveals a link between developmental states and ribosomal protein expression as a source of intra-individual heterogeneity.

Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer. It is characterized by bone marrow lymphoid precursors that acquire genetic alterations, resulting in disrupted maturation and uncontrollable proliferation. More than a dozen molecular subtypes of variable severity can be used to classify cALL cases.

Circulating let-7g-5p and miR-191-5p Are Independent Predictors of Chronic Kidney Disease in Hypertensive Patients.

Background: Hypertension (HTN) is associated with target organ damage such as cardiac, vascular, and kidney injury. Several studies have investigated circulating microRNAs (miRNAs) as biomarkers of cardiovascular disease, but few have examined them as biomarker of target organ damage in HTN. We aimed to identify circulating miRNAs that could serve as biomarkers of HTN-induced target organ damage using an unbiased approach.

Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

Background: Cardiac glycosides are approved for the treatment of heart failure as Na/K pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized.

miR-431-5p Knockdown Protects Against Angiotensin II-Induced Hypertension and Vascular Injury.

Vascular injury is an early manifestation in hypertension and a cause of end-organ damage. MicroRNAs play an important role in cardiovascular disease, but their implication in vascular injury in hypertension remains unclear. This study revealed using an unbiased approach, microRNA and mRNA sequencing with molecular interaction analysis, a microRNA-transcription factor coregulatory network involved in vascular injury in mice made hypertensive by 14-day Ang II (angiotensin II) infusion.

Recurrent somatic BRAF insertion (p.V504_R506dup): a tumor marker and a potential therapeutic target in pilocytic astrocytoma.

Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication.

Very long intergenic non-coding RNA transcripts and expression profiles are associated to specific childhood acute lymphoblastic leukemia subtypes.

Very long intergenic non-coding RNAs (vlincRNAs) are a novel class of long transcripts (~50 kb to 1 Mb) with cell type- or cancer-specific expression. We report the discovery and characterization of 256 vlincRNAs from a cohort of 64 primary childhood pre-B and pre-T acute lymphoblastic leukemia (cALL) samples, of which 61% are novel and specifically expressed in cALL. Validation was performed in 35 pre-B and pre-T cALL primary samples.

Genome wide mapping of ETV6 binding sites in pre-B leukemic cells.

Genetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(12;21) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function.

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy.

Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Refractory/relapsed cALL presents a survival rate of ∼45% and is still one of the leading causes of death by disease among children. Mechanisms, such as clonal competition and evolutionary adaptation, govern treatment resistance.

LncRNAs downregulated in childhood acute lymphoblastic leukemia modulate apoptosis, cell migration, and DNA damage response.

Childhood acute lymphoblastic leukemia (cALL) accounts for 25% of pediatric cancers and is one of the leading causes of disease-related death in children. Although long non-coding RNAs (lncRNAs) have been implicated in cALL etiology, progression, and treatment response, little is known about their exact functional role. We had previously sequenced the whole transcriptome of 56 cALL patients and identified lncRNA transcripts specifically silenced in tumoral cells.

Specific expression of novel long non-coding RNAs in high-hyperdiploid childhood acute lymphoblastic leukemia.

Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome.

A childhood acute lymphoblastic leukemia-specific lncRNA implicated in prednisolone resistance, cell proliferation, and migration.

Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer and, despite an 85% cure rate, still represents a major cause of disease-related death in children. Recent studies have implicated long non-coding RNAs (lncRNAs) in cALL etiology, progression, and treatment response. However, barring some exceptions little is known about the functional impact of lncRNAs on cancer biology, which limits their potential as potential therapeutic targets.

SNooPer: a machine learning-based method for somatic variant identification from low-pass next-generation sequencing.

Background: Next-generation sequencing (NGS) allows unbiased, in-depth interrogation of cancer genomes. Many somatic variant callers have been developed yet accurate ascertainment of somatic variants remains a considerable challenge as evidenced by the varying mutation call rates and low concordance among callers. Statistical model-based algorithms that are currently available perform well under ideal scenarios, such as high sequencing depth, homogeneous tumor samples, high somatic variant allele frequency (VAF), but show limited performance with sub-optimal data such as low-pass whole-exome/genome sequencing data.

Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined.