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PubMed2026

A Combination of Alleles in LMOD2 and a lncRNA is Strongly Associated With Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels.

A previous genome-wide association study identified regions on canine chromosome (cfa) 13 and 14 associated with early onset myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS). In the present study, whole genome sequencing (WGS) of 9 CKCS cases (mitral regurgitation (MR) before 4.5 years or congestive heart failure (CHF) at any age due to MMVD) and 10 CKCS controls (no or mild MR after 8 years of age) identified > 2000 genetic variants in the MMVD associated cfa13 and cfa14 regions. Ensembl Variant Effect Predictor (VEP) identified a possible functional impact of 18 variants. These were genotyped in 250 CKCS; 117 cases and 133 controls. The most significantly associated variants were a splice-site variant in a long noncoding RNA (lncRNA) on cfa13, a nonsynonymous variant in HYAL4, a 39 base-pair insertion in LMOD2 and a synonymous variant in ENSCAFG00000024436 (p-values from 2.03E-08 to 4.20E-06). Concomitant homozygosity for risk alleles in LMOD2 and the lncRNA gave an odds-ratio for MMVD of 52.5 compared to homozygosity for the nonrisk alleles (p = 0.00034, 95% CI: 8.8-1023.8). Upon validation of our results in an independent cohort, this gene variant combination in CKCS is expected to enable targeted breeding programs to reduce MMVD prevalence in CKCS.

Animals↗

PubMed2026

A Proteogenomic Approach to Discover Novel lncRNA-Derived Microproteins and Their Potential Clinical Utility in Hepatocellular Carcinoma.

Microproteins (i.e., peptides) are increasingly recognized for their functions in versatile biological contexts, but their clinical relevance and utility remain largely unexplored. Proteogenomic approaches can accelerate microprotein discovery in clinical samples by integrating proteomic data with genomics and transcriptomics evidence. However, long noncoding RNA (lncRNA)-derived microproteins (lncPeps) remain largely unidentified, resulting in unmatchable MS/MS spectra. To solve this problem, we have used high-quality Ribo-seq translatomic datasets to generate an extensive database of human liver lncRNA-derived open reading frames (lncORFs), which we subsequently applied to proteomics data of tumor-adjacent normal tissue pairs from hepatocellular carcinoma (HCC) patients. Using the new database, we discovered 104 novel lncPeps, including 46 lncPeps differentially expressed between tumor and nontumor tissues, and 13 lncPeps with significant correlation with prognosis. Remarkably, combining the expression of lncPeps with canonical proteins in a LASSO regression model improved predictive performance for recurrence, increasing the AUC by 0.005 to 0.085 across three recurrence time points. These findings suggest that the discovery of lncPeps contributes to our understanding of the molecular heterogeneity and progression of HCC and broadens the range of potential biomarker candidates and treatment targets for the disease.

Humans↗

PubMed2025

MEG3 Promoter Methylation and F11 Receptor (F11R) Overexpression Define a High-Risk Subtype of Diabetic Pancreatic Cancer.

Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (MEG3) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of MEG3 was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. MEG3 expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. MEG3 promoter methylation was more prevalent in patients with long-DM. MEG3 methylation was correlated with reduced MEG3 expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of MEG3. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous MEG3 methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that MEG3 and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as MEG3 and F11R, for potential therapeutic intervention.

Humans↗

PubMed2025

LncRNA C5orf64 polymorphisms (rs12518552 and rs2950218) decreases pulmonary tuberculosis susceptibility.

BACKGROUND: Pulmonary tuberculosis (PTB) remains a significant global health issue, with genetic factors playing a crucial role in susceptibility. Long noncoding RNA (lncRNA) C5orf64 has been implicated in immune responses and cancer, but its association with PTB risk has not been fully explored. METHODS: Genomic DNA was extracted from peripheral blood samples of 955 participants (474 PTB cases and 481 controls). Rs12518552 and rs2950218 in C5orf64 were genotyped using the Agena MassARRAY system. Logistic regression analysis was performed to assess the association between these polymorphisms and PTB risk. Stratified analysis was conducted to evaluate the influence of age, gender, and smoking status. RESULTS: Rs12518552-G (OR = 0.82, p = 0.034) and rs2950218-T (OR = 0.77, p = 0.012) were associated with a reduced PTB risk. Stratified analysis revealed that rs12518552 was associated with a protective effect against PTB in individuals over 40 years old (OR = 0.73, p = 0.024), females (OR = 0.77, p = 0.034), and non-smokers (OR = 0.78, p = 0.040), and rs2950218 was also associated with a reduced PTB risk in individuals over 40 years old (OR = 0.73, p = 0.040), females (OR = 0.72, p = 0.046), and non-smokers (OR = 0.72, p = 0.011). CONCLUSION: C5orf64 polymorphisms, particularly rs12518552 and rs2950218, are associated with a reduced risk of PTB. These findings suggest that C5orf64 polymorphisms contribute to genetic susceptibility to PTB, with implications for PTB targeted screening and personalized therapeutic strategies.

Humans↗

PubMed2025

Genetic mapping in the red mason bee implicates ANTSR as an ancient sex-determining locus in bees and ants.

Haplodiploid inheritance, in which females are diploid and males are haploid, is found in all species of Hymenoptera. Sex in haplodiploids is commonly determined by the alleles present at a complementary sex determination (CSD) locus, with heterozygosity triggering the female developmental pathway. The identity of this locus differs among taxa and is only known in a few species. Here, we map a single CSD locus to a 2 kbp region in the genome of the red mason bee Osmia bicornis. It overlaps the long noncoding RNA ANTSR, which has been identified as the sex-determining gene in the invasive ant Linepithema humile. This locus is homozygous in diploid males and exhibits extremely high levels of haplotype diversity, consistent with the action of frequency-dependent selection. The elevated levels of heterozygosity in the CSD locus enable us to fine-map potentially functional genetic variation within it. We also identify elevated levels of genetic diversity in the ortholog of the CSD locus in five other bee and ant genera, suggesting that it may govern sex determination widely in Hymenoptera. Our data are consistent with the hypothesis that ANTSR evolved a role in sex determination over 150 million years ago and is the ancestral sex-determination locus of bees and ants.

Animals↗

PubMed2025

DIS3 licenses B cells for plasma cell differentiation in humans.

DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.

Humans↗

PubMed2025

Long non-coding RNA NEAT1 promotes colorectal cancer progression via interacting with SIRT1.

Nuclear-enriched abundant transcript 1 (NEAT1), a long noncoding RNA, is found to be significantly dysregulated in different types of cancer, including colorectal cancer (CRC). Nevertheless, there is still much to learn about the precise functions and processes of NEAT1 in the progression of CRC. Using The Cancer Genome Atlas (TCGA) database and 50 CRC specimens from the First Affiliated Hospital of Dali University, we assessed the expression of NEAT1 to determine its clinical impact. Through gene set enrichment analysis (GSEA), Cancer Single-cell State Atlas (CancerSEA), and immune infiltration studies, we elucidated key functions of NEAT1. We utilized Cell Counting Kit-8 (CCK8), wound healing, and Transwell assays to investigate the role of NEAT1 in the progression of CRC. Through the use of GSEA and immunohistochemistry, additional investigations were conducted to unveil the downstream targets of NEAT1 and gain insights into their regulatory dynamics. Our in vitro studies confirmed the regulatory role of NEAT1 in CRC. Findings indicate that increased NEAT1 expression correlates with adverse outcomes in colorectal tissues. In the CRC model, reduced levels of NEAT1 lead to reduced cell proliferation, invasion, and migration. Additionally, NEAT1 influenced immune cell infiltration in CRC and functioned as an oncogene by upregulating Sirtuin 1 (SIRT1) expression. This study demonstrates that NEAT1 promotes CRC progression and metastasis through a SIRT1-mediated mechanism, suggesting its potential as a prognostic biomarker and therapeutic target for CRC.

RNA, Long Noncoding↗

PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗

PubMed2025

An RNA polymerase III tissue and tumor atlas uncovers context-specific activities linked to 3D epigenome regulatory mechanisms.

RNA polymerase III (Pol III) produces a plethora of small noncoding RNA species involved in diverse cellular processes, from transcription regulation and splicing to RNA stability, translation, and proteostasis. Though Pol III activity is broadly coupled with cellular demands for protein synthesis and growth, a more precise understanding of gene-level dynamics and context-specific expression patterns remains missing, in part due to challenges related to sequencing and mapping Pol III-derived small ncRNAs. Here, we establish a predictive multi-tissue map of human Pol III activity across 19 tissues and 23 primary cancer subtypes by comprehensively profiling the chromatin accessibility of canonical Pol III-transcribed gene classes. Our framework relies on the unique relationship between gene accessibility and Pol III transcription, inferring activity through uniform binary classification of ATAC-seq enrichment at Pol III-transcribed genes. By characterizing multi-context gene uniformity, we provide a definition of the core Pol III transcriptome, broadly active across specialized tissues, and catalog genes with varied levels of context specificity. Our genomic Pol III atlas uncovers variable levels of activity across tissues, including sharp contraction of the Pol III transcriptome in heart and brain tissues and frequent expansion across diverse cancers. We show that both tissue- and tumor-specific genes are significantly enriched within lamina-associated domains (LADs), and that aberrant expression of nuclear lamin proteins is sufficient to induce Pol III-emergent patterns at tumor-specific genes. Together, these findings link Pol III dynamics to subnuclear compartmentalization and provide a resource for better understanding Pol III expansion and small RNA biogenesis in cancer.

Journal Article↗

PubMed1978

Nucleotide sequence at the 5' extremity of tobacco-mosaic-virus RNA. 1. The noncoding region (nucleotides 1-68).

The sequence of the 5' noncoding region of tobacco mosaic virus RNA has been determined. The noncoding region is 68 nucleotides long and is unusual in that it contains no internal guanosine residues. The long T1 oligonucleotide containing the guanosine-free tract was isolated from a T1 ribonuclease digest of tobacco mosaic virus RNA and sequenced by labelling techniques in vitro using polynucleotide kinase. The guanosine-free tract is terminated by the first potential initiation codon in the RNA molecule and several lines of evidence suggest that this AUG triplet is operational in initiating viral protein synthesis (see following paper). The 5'-noncoding region cannot base-pair extensively with the 3'-terminal sequence of 18-S ribosomal RNA from rabbit reticulocytes.

Base Sequence↗

PubMed2026

Rop-Mediated Suppression of RpoS Production Increases Resistance to Nitric Oxide.

We identified the RNA-binding protein Rop, encoded on the pOSAK1 plasmid of enterohaemorrhagic Escherichia coli (EHEC), as a novel factor that enhances nitric oxide (NO) resistance, although it has previously been reported to regulate plasmid copy number. The Rop-induced increase in NO resistance was significantly reduced in several small noncoding RNA (sRNA) gene-deficient EHEC mutants. Among these sRNAs, DsrA, ArcZ, and RprA were directly involved in the translational regulation of rpoS expression, suggesting that Rop modulates rpoS expression through sRNAs. To examine this mechanism, we generated sRNA gene-deficient mutants with an additional deletion of the 5' untranslated region (5' UTR) of rpoS, which is required for translational regulation. The increase in NO resistance by Rop was restored in the double mutant, suggesting that this phenotype is mediated by Rop-dependent interactions between sRNAs and the 5' UTR of rpoS mRNA. Furthermore, Rop promoted rpoS mRNA degradation, an effect that likely suppresses RpoS production and may thereby enhance NO resistance. Finally, an hfq-deficient EHEC mutant exhibited no increase in NO resistance in the presence of Rop, indicating that Hfq is essential for Rop-mediated NO resistance.

Nitric Oxide↗

PubMed2025

Identification and Analysis of Small Nucleolar RNAs by Real-Time Quantitative PCR.

One of the greatest scientific achievements of the twenty-first century is the completion of The Human Genome Project (HGP). Thereafter, we came to know that the human genome codes nearly 2% for making proteins and thus named as coding genes, suggesting the rest of the genome as noncoding or junk. However, research in the past two decades has shown and established that noncoding RNAs are major contributors of regulating and modulating the various function of cells as well as tissues. Noncoding RNAs can be classified as basis of their sizes in two categories, long noncoding RNAs (>200 nt) and small noncoding RNAs (<200 nt). Small nucleolar RNAs (snoRNAs) are part of the small noncoding RNA family and primarily reside inside the nucleus of eukaryotes. Sno RNAs can be divided into two major categories based on their distinguished structure and function; these are C/D box and HACA box snoRNAs. They participate in the posttranscriptional modifications on ribosomal RNAs (r-RNAs), transfer RNAs (t-RNAs), messenger RNAs (m-RNAs), and small nuclear RNAs (snRNAs). Sno RNAs act as guide RNAs to modify other noncoding RNAs by pseudouridylation or 2'O ribomethylation. We discussed in this protocol about one of the widely used techniques for detection and analysis of snoRNAs, i.e., real-time quantitative PCR (RT-qPCR).

RNA, Small Nucleolar↗

PubMed1978

Transcription termination: nucleotide sequence at 3' end of tryptophan operon in Escherichia coli.

We have determined the RNA and DNA sequences in the region specifying termination of transcription at the end of the tryptophan (trp) operon of Escherichia coli. A 3'-terminal mRNA fragment of about 150 nucleotides yielded oligonucleotide products that could be assigned to the end of trpA (the last structural gene in the operon) by correlation with the amino acid sequence of the protein product. Analysis of the DNA corresponding to this region served to align the few noncoding RNA oligonucleotide sequences and demonstrated that termination of trp transcription occurs in vivo at a site 36 nucleotides after trpA, with greater than 95% efficiency. In two different strains partially defective in the transcription termination factor rho, the purified transcript is much longer and more complex, suggesting that a significant amount of read-through occurs in these strains. This is consistent with evidence [Guarente, L. P., Mitchell, D. H. & Beckwith, J. (1977) J. Mol. Biol. 112, 423-436] that efficient termination in vivo at the end of the trp operon is a rho-dependent event. The trp terminator (trp t) shares several features with other known sites of transcription termination, including (i) a 3'-terminal RNA sequence of several uridine residues, C-A-U-U-U-U(OH), (ii) a G.C-rich region in the DNA immediately preceding the site of termination, followed by an A.T-rich region, and (iii) a region of dyad symmetry in the DNA which, in the transcript, is capable of forming a stable hairpin containing seven G.C base pairs and one A.U base pair in its stem.

Base Sequence↗

PubMed2026

Functional characterization of lncIMF_17214 in regulating intramuscular fat deposition of yellow-feathered broilers.

Intramuscular fat (IMF) content and lipid composition are key determinants of both the nutritional value and sensory attributes of poultry meat, yet the underlying regulatory mechanisms remain insufficiently elucidated. In this study, triglyceride (TG) content was employed as a quantitative phenotypic proxy to dissect the molecular basis of IMF deposition in yellow-feathered broilers. By integrating TG phenotypic data from 315 individuals with transcriptomic profiles and whole-genome resequencing datasets, a TG-associated long noncoding RNA (lncRNA), lncIMF_17214, was identified. Functional characterization revealed that lncIMF_17214 functions as a negative regulator of lipid deposition. Specifically, its knockdown led to significant increases in TG and total cholesterol concentrations, promoted lipid droplet accumulation, and decreased shear force in breast muscle, whereas its overexpression elicited the opposite effects. Mechanistically, lncIMF_17214 interacts with the RNA-binding protein CNBP, forming a regulatory complex that inhibits lipid accumulation. Furthermore, liver-directed overexpression increased the abundance of lncIMF_17214 in plasma exosomes, while liver-directed manipulation was associated with changes in hepatic and breast-muscle lipid deposition; direct exosome-mediated transfer to intramuscular adipocytes remains to be established. Transcriptomic profiling coupled with pathway enrichment analyses demonstrated that lncIMF_17214 predominantly influences steroid biosynthesis, unsaturated fatty acid metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. This suggests that it may be involved in the regulation of these pathways, although the underlying molecular mechanisms remain to be further elucidated. Collectively, these findings define a lncIMF_17214-centered regulatory axis linking intracellular and systemic lipid metabolism and provide a robust molecular framework for the targeted improvement of meat quality traits in yellow-feathered broilers.

Breast muscle↗

PubMed2024

Reducing competition between msd and genomic DNA improves retron editing efficiency.

Retrons, found in bacteria and used for defense against phages, generate a unique molecule known as multicopy single-stranded DNA (msDNA). This msDNA mimics Okazaki fragments during DNA replication, making it a promising tool for targeted gene editing in prokaryotes. However, existing retron systems often exhibit suboptimal editing efficiency. Here, we identify the msd gene in Escherichia coli, which encodes the noncoding RNA template for msDNA synthesis and carries the homologous sequence of the target gene to be edited, as a critical bottleneck. Sequence homology causes the msDNA to bind to the msd gene, thereby reducing its efficiency in editing the target gene. To address this issue, we engineer a retron system that tailors msDNA to the leading strand of the plasmid containing the msd gene. This strategy minimizes msd gene editing and reduces competition with target genes, significantly increasing msDNA availability. Our optimized system achieves very high retron editing efficiency, enhancing performance and expanding the potential for in vivo techniques that rely on homologous DNA synthesis.

Gene Editing↗

PubMed2026

Evolutionary constraints and regulatory plasticity shape host specialization in the Magnaporthe oryzae species complex.

Rice blast caused by Magnaporthe oryzae threatens global rice production, and wheat blast emergence highlights the pathogen's capacity for host shifts. Although numerous studies have described M. oryzae genome organization and infection mechanisms, critical questions remain regarding the evolutionary drivers of stable host specialization. Importantly, the blast pathogen comprises a species complex of genetically differentiated, host-adapted lineages rather than single homogeneous species. To address this knowledge gap, we integrate evidence from evolutionary genomics, transcriptomics, and metabolomics to develop the "Constrained Plasticity" framework. We argue that host adaptation arises from three interacting layers: genomic scaffolding (including epigenetic and noncoding RNA regulation), regulatory networks (enabling transcriptional plasticity), and metabolic compatibility (determining physiological success). This systems-level perspective explains the long-term stability of host-adapted lineages and the rare breakdowns resulting in host shifts, such as wheat blast. This framework generates testable predictions for pathogen emergence and provides a roadmap for developing lineage-aware resistance strategies.

Oryza↗

PubMed2018

Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone.

Corticosteroids are highly prescribed and effective anti-inflammatory drugs but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use is an important goal for treatment of chronic inflammatory diseases such as Duchenne muscular dystrophy (DMD). We have developed vamorolone (VBP15), a first-in-class dissociative glucocorticoid receptor (GR) ligand that shows the anti-inflammatory efficacy of corticosteroids without key steroid side effects in animal models. miRNAs are increasingly recognized as key regulators of inflammatory responses. To define effects of prednisolone and vamorolone on the muscle miRNAome, we performed a preclinical discovery study in the mdx mouse model of DMD. miRNAs associated with inflammation were highly elevated in mdx muscle. Both vamorolone and prednisolone returned these toward wild-type levels (miR-142-5p, miR-142-3p, miR-146a, miR-301a, miR-324-3p, miR-455-5p, miR-455-3p, miR-497, miR-652). Effects of vamorolone were largely limited to reduction of proinflammatory miRNAs. In contrast, prednisolone activated a separate group of miRNAs associated with steroid side effects and a noncoding RNA cluster homologous to human chromosome 14q32. Effects were validated for inflammatory miRNAs in a second, independent preclinical study. For the anti-inflammatory miRNA signature, bioinformatic analyses showed all of these miRNAs are directly regulated by, or in turn activate, the inflammatory transcription factor NF-κB. Moving forward miR-146a and miR-142 are of particular interest as biomarkers or novel drug targets. These data validate NF-κB signaling as a target of dissociative GR-ligand efficacy in vivo and provide new insight into miRNA signaling in chronic inflammation.

Animals↗

PubMed2026

Deregulation of FOXF1/FENDRR from t(14;16)(q32;q24) defines a subtype of high-risk lineage ambiguous leukemia.

Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage, there are still cases that lack defining genetic markers, complicating risk stratification, and limiting targeted therapeutic options. Recent studies have shown that enhancer hijacking drives oncogene activation in approximately half of T-ALL cases, with the BCL11B (BCL11 transcription factor B) enhancer frequently involved. Here, we describe a subtype of leukemia with a distinct gene-expression signature, and immunophenotype characterized by positivity for immature (CD38), myeloid (CD13), T-lymphoid (cytoplasmic [c]CD3, CD7), and B-lymphoid markers (CD19, CD79a, CD10). This subtype is defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Common concomitant genetic lesions are loss-of-function alterations of GATA3, CDKN2A/CDKN2B deletion and activating JAK/STAT and NOTCH1 pathway mutations. Patients were predominantly children and adolescents/young adults and experienced poor treatment outcome. High-throughput drug screening of 176 compounds demonstrated efficacy of combined BCL2 apoptosis regulator family proteins and JAK/STAT signaling inhibitors. Additionally, the clinical use of tyrosine kinase inhibitors in some of these patients showed therapeutic efficacy. Collectively, these findings identify BCL11B-enhancer-mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.

Humans↗