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The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy.

EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma),

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… a key role in the 3’cleavage and polyadenylation of pre-mRNA ( 36 , 37 ). … Characterization of cleavage and polyadenylation specificity factor and cloning of its 100-kilodalton subunit. Mol Cell Biol (1994) 14(12):8183–90. doi: 10.1128/mcb.14.12.8183-8190.1994 37. Sasado T, Kondoh H, Furutani-Seiki M, Naruse K. …

The Biogenesis and Functions of piRNAs in Human Diseases.

Piwi-interacting RNAs (piRNAs) are a novel type of small noncoding RNAs, which are 26-30 nt in length and bind to Piwi proteins. These short RNAs were originally discovered in germline cells and are considered as key regulators for germline maintenance. A growing body of evidence has now extended our views into piRNA biological significance showing that they can also regulate gene expression in somatic cells through transposon silencing, epigenetic programming, DNA rearrangements, mRNA turnover, and translational control. Mounting studies have revealed that the dysregulation of piRNAs may caus

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… Dual-strand clusters (right) have no distinct promoter regions and generate non-polyadenylated piRNA precursors from two directions. … Rhi binds to the H3K9me3 mark and inhibits transcript splicing, as well as represses the use of canonical cleavage and polyadenylation sequence motifs. Cuff prevents premature termination and protects RNA from degradation. …

Current Advances in RNA Therapeutics for Human Diseases.

Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairl

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… RNase H independent/steric block ASOs are typically composed of only RNA and act by binding directly to the target pre-mRNA or mature mRNA to cause inhibition of mRNA translation ( Figure 1 B), alternative splicing, promotion of mRNA translation, or alternative polyadenylation. … ASOs have also been shown to cause alternative polyadenylation by blocking certain polyadenylation sites [ 101 ]. This commonly leads to shorter transcripts that contain less destabilized segments, typically leading to increased stability of the mRNA. …

Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics.

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18-21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normal

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… Prior to protein synthesis, mRNA undergoes a range of essential processing steps such as 5′-capping, polyadenylation, intron—exon splicing, nuclear export, cytoplasmic stabilization and ribosomal binding. … Likewise, polyadenylation is essential for the stability and transport of mRNA. Therefore, As-ODNs designed against the 5′ or 3′ region of pre-mRNA can prevent its capping or Polyadenylation, resulting in the destabilization and disintegration of mRNA [ 17 ]. …

miRNA-seq identification and clinical validation of CD138+ and circulating miR-25 in treatment response of multiple myeloma.

BackgroundDespite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients' management.MethodsmiRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69)

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… Polyadenylation of total RNA and first-strand cDNA synthesis Total RNA was polyadenylated at 3-end in a 10 µL reaction, containing 200 ng of total RNA from CD138+ plasma cells or 2 µL total RNA from plasma samples, 1 U of recombinant E.coli Poly(A) Polymerase (New England Biolabs Inc., Ipswich, MA, … Following polyadenylation, reverse transcription of the RNA was performed in a 20 μL reaction containing 200 U M-MLV Reverse Transcriptase (Invitrogen), 40 U RNaseOUT Recombinant Ribonuclease Inhibitor (Invitrogen), 10 mM dNTP Mix and 250 mM oligo-dT adapter 5′-GCGAGCACAGAATTAATACGACTCACTATAGGTTTTTTTTTTTTVN …

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells.

Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a l

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… The therapeutic applications of cordycepin have been reported from the perspective of several physiological processes, including those incorporating mRNA polyadenylation inhibitory [ 44 ], anti-inflammatory [ 45 ], anti-tumor [ 19 ], and anti-cancer properties [ 46 ]. … The effect of the polyadenylation inhibitor cordycepin on human Molt-4 and Daudi leukaemia and lymphoma cell lines. Cancer Chemother. Pharmacol. 2008;61:703–711. doi: 10.1007/s00280-007-0533-5. 45. Tan L., Song X., Ren Y., Wang M., Guo C., Guo D., Gu Y., Li Y., Cao Z., Deng Y. …

KIAA1429-mediated M6A methylation inhibits osteoclast differentiation via stabilizing Lrp4 mRNA and protects against osteoporosis.

N6-methyladenosine (m6A) is a novel epigenetic modification that has been reported to be involved in the progression of osteoporosis (OP), providing new insights into the pathogenesis of OP. The methyltransferases KIAA1429 [also known as virus-like m6A methyltransferase-associated protein (VIRMA)] participates in various essential biological processes by regulating target gene expression levels. However, the function of KIAA1429-mediated m6A modification in OP progression remains unclear. This study aimed to investigate the biological roles and potential underlying mechanisms of KIAA1429 in OP

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… As a common epigenetic modification in eukaryotes, N 6 -methyladenosine (m 6 A) methylation modification plays important functions in mRNA splicing, editing, stability, degradation, and polyadenylation [ 20 – 22 ]. … Polyadenylated mRNA purification employed the Arraystar Seq-Star™ isolation kit (Aksomics, China), followed by m⁶A-methylated RNA enrichment with anti-m⁶A antibody (Abcam, no. ab286164, UK). …

Epigenetic and Genetic Keys to Fight HPV-Related Cancers.

Cervical cancer ranks as the fourth most prevalent cancer among women globally, with approximately 600,000 new cases being diagnosed each year. The principal driver of cervical cancer is the human papillomavirus (HPV), where viral oncoproteins E6 and E7 undertake the role of driving its carcinogenic potential. Despite extensive investigative efforts, numerous facets concerning HPV infection, replication, and pathogenesis remain shrouded in uncertainty. The virus operates through a variety of epigenetic mechanisms, and the epigenetic signature of HPV-related tumors is a major bottleneck in our

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… Figure 1 HPV features. ( A ) Structure of the capsid. ( B ) The genome is represented in a linear fashion with the positions of the viral early (PromAE) and late (PromAL) promoters, early (pAE) and late (pAL) polyadenylation signals; below are the predicted viral ORFs with the positions of the nucleotides … These three regions are divided by two polyadenylation (pA) sites: early pA (AE) sites and late pAL (AL) sites [ 20 ]. …

MicroRNAs in B-cells: from normal differentiation to treatment of malignancies.

MicroRNAs (miRNAs) are small non-coding RNAs that play important post-transcriptional regulatory roles in a wide range of biological processes. They are fundamental to the normal development of cells, and evidence suggests that the deregulation of specific miRNAs is involved in malignant transformation due to their function as oncogenes or tumor suppressors. We know that miRNAs are involved in the development of normal B-cells and that different B-cell subsets express specific miRNA profiles according to their degree of differentiation. B-cell-derived malignancies contain transcription signatu

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… In the canonical biogenesis pathway, intergenic miRNA genes are transcribed by RNA polymerase II into 5′-capped and 3′-polyadenylated molecules, the primary-miRNAs [ 17 ]. … The impact of miRNA regulation of gene expression is illustrated in a more indirect manner when cancer cells truncate the 3′ UTR of target mRNAs by alternative polyadenylation, thus avoiding miRNA regulation [ 88 , 89 ]. …

MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators.

A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregu

Opinion: more mouse models and more translation needed for ALS.

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potenti

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… Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019;22(2):180–90. doi: 10.1038/s41593-018-0293-z. 15. Ma XR, et al. TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. … Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science. 2023;379(6637):1140–9. doi: 10.1126/science.abq5622. 18. Rolfes L, et al. Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation. …

Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

As the role of RNA modification in gene expression regulation and human diseases, the "epitranscriptome" has been shown to be an important player in regulating many physiological and pathological processes. Meanwhile, the phenomenon of cancer drug resistance is becoming more and more frequent, especially in the case of cancer chemotherapy resistance. In recent years, research on relationship between post-transcriptional modification and cancer including drug resistance has become a hot topic, especially the methylation of the sixth nitrogen site of RNA adenosine-m6A (N6-methyladenosine). m6A m

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… Methylation in the 5’UTR region of mRNA plays an important role in mRNA splicing, editing, stability, degradation, polyadenylation, etc., while modification in the 3’UTR region contributes to the nuclear export of mRNA, initiation of translation, and maintenance of mRNA structural stability [ 35 ]. … 297 ] UZH1a 7μM Dose-dependent inhibition of m 6 A methylation levels in HEK293T and U2OS cells, selective inhibition of RNA methyltransferase. [ 299 ] Elvitegravir 10μM Enhancing STUB1-mediated proteasome degradation of METTL3, suppresses ESCC metastatic. [ 301 ] UZH2 5nM Reduce m 6 A/A levels of polyadenylated …

Gene therapy of rare diseases as a milestone in medicine - overview of the field and report on initial experiences in Slovenia.

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients' lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field s

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… Fig. 1 Gene addition approaches versus targeted genome editing approaches. ( A ) During gene addition, viral vectors, including AAV vectors, RV/LV vectors, AdV vectors, and non-viral vectors (e.g., LNPs), deliver a whole gene of interest with promoter or enhancer elements and polyadenylation signals. … permission from Elsevier Fig. 1 Gene addition approaches versus targeted genome editing approaches. ( A ) During gene addition, viral vectors, including AAV vectors, RV/LV vectors, AdV vectors, and non-viral vectors (e.g., LNPs), deliver a whole gene of interest with promoter or enhancer elements and polyadenylation …

CircRNA ITCH: Insight Into Its Role and Clinical Application Prospect in Tumor and Non-Tumor Diseases.

CircRNA E3 ubiquitin protein ligase (ITCH) (circRNA ITCH, circ-ITCH), a stable closed-loop RNA derived from the 20q11.22 region of chromosome 20, is a new circRNA discovered in the cytoplasm in recent decades. Studies have shown that it does not encode proteins, but regulates proteins expression at different levels. It is down-regulated in tumor diseases and is involved in a number of biological activities, including inhibiting cell proliferation, migration, invasion, and promoting apoptosis. It can also alter disease progression in non-tumor disease by affecting the cell cycle, inflammatory r

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… The ID number of circ-ITCH is hsa_circ_0001141, whose gene is located in chr 20q11.22, derived from exon 6–13 of ITCH coding gene, formed by back-splicing, and its mature sequence is 873bp. 2 Regulation Mechanism and Role of Circ-ITCH in Tumor Diseases MiRNA, as a part of the ceRNA network, causes polyadenylation … Cytoplasmic polyadenylation element binding protein 3 (CPEB3), a RNA binding protein, plays a tumor-suppressive role though regulating the expression of malignant transformation-related genes through post-transcriptional control ( Pichon et al., 2012 ). …

Investigation of Some Long Noncoding RNAs (LncRNAs) in Pediatric Inflammatory Bowel Disease (IBD): An Iranian Study.

Introduction: According to the importance of long noncoding RNAs (LncRNA) in the pathogenesis of inflammatory bowel disease (IBD) and also the lack of study for pediatric IBD in this regard, we investigated the expression of a selected panel of LncRNAs in Iranian pediatric cases of IBD compared to adult cases and healthy samples. Methods: In this gene expression study, blood samples were taken from the three groups of pediatric IBD cases, adult IBD cases, and pediatric healthy samples (for gene expression calibration). The investigated LncRNAs were UCA1, CCAT, IFNG-AS1, and CDKN2B. Real-time P

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… LncRNAs, like mRNAs, are transcribed by RNA polymerase II, and after transcription, capping and polyadenylation processes occur in them [ 2 – 4 ]. …

Alternative Splicing: A Critical Regulator in Human Bone Biology and Tumor Progression.

Alternative splicing (AS) is the central mechanism of transcriptional regulation and generates diverse splice variants that influence protein structure, function, and intracellular activity. AS plays critical roles in tissue differentiation, organ development, and disease progression. This review focuses on the pivotal roles of AS in bone biology, highlighting its regulatory effects on osteoblasts, osteoclasts, chondrocytes, bone matrix remodeling, and bone remodeling, as well as the involvement of AS-related RNA-binding proteins in these processes. We also emphasize bone-specific AS events an

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… The pre-mRNA is a primary transcript, which is transcribed and synthesized by the DNA template in the nucleus, and mRNA is formed through the processes of 5′-cap addition, splicing, editing, and polyadenylation. … (B) Overview of major alternative splicing patterns, including exon skipping/inclusion, intron retention, alternative 5′ and 3′ splice site usage, MXE, and regulation by APs or polyadenylation sites. …

Perturbing Enhancer Activity in Cancer Therapy.

Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation.

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… These phosphorylation events release Pol II from promoter proximal pausing and allow transcription elongation until polyadenylation sequences are transcribed, which leads to the cleavage and subsequent polyadenylation of mRNAs [ 117 ]. …

Человеческие эндогенные ретровирусы как новые терапевтические цели в нейродегенеративных расстройствах.

Человеческие эндогенные ретровирусы составляют приблизительно 8% генома человека и служат фрагментами древних антиретровирусных инфекций. Хотя они, как правило, удерживаются в замалчиваемом состоянии с помощью надежных эпигенетических механизмов, конкретные группы HERV, в частности HERV-W и HERV-K, могут депрессировать в конкретных патологических условиях, что способствует инициированию и продвижению нейро-воспалительных и нейродегенеративных процессов. Доклинические исследования и клинические испытания, такие, как исследования моноклонных антител, показывают, что прямая ориентация на эти элем

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… Despite their generally dormant state, several HERVs retain intact or partially intact regulatory sequences, such as promoters, enhancers, and polyadenylation signals, as well as, in some circumstances, open reading frames (ORFs) capable of generating functional transcripts and proteins [ 5 ]. …

An Overview of Bortezomib-Induced Neurotoxicity.

The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often induces a dose-limiting toxicity in the form of painful sensory neuropathy, which can mainly be reduced by subcutaneous administration or dose modification. In this review we focus on the current understanding of the pathophysiological mechanisms of bortezomib-induced neuropathy to allow further studies in

NEAT1 lncRNA overexpression results in short-term progression and poor treatment outcome in childhood B-ALL.

Childhood acute lymphoblastic leukaemia (chALL) remains the most prevalent malignancy in children and adolescents. Improving risk stratification and providing personalized prognosis and treatment remain major clinical challenges. Herein, we analysed the clinical utility of NEAT1 lncRNA for the prognosis and prediction of treatment outcome of childhood B-cell precursor ALL (chB-ALL). NEAT1_1 isoform was quantified in bone marrow samples of chB-ALL patients at diagnosis (n = 160) and at the end of induction (n = 108) of ALL-BFM protocol, and in age-matched healthy children (n = 68). Relapse and

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… the NEAT1 gene locus produces two transcripts, the short NEAT1_1 (3.7 kb) and the long NEAT1_2 (22.7 kb) isoforms, that share the same transcriptional start site; however, they undergo altered 3′‐end processing. 23 , 28 The shorter NEAT1_1 transcripts result from canonical RNA processing and 3′‐end polyadenylation …