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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%–70%) and alveolar RMS (aRMS; 20%–30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion‐positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion‐negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long‐term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments. [ABSTRACT FROM AUTHOR]

Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. However, other genetic and epigenetic abnormalities in SS do not necessarily include SS18-SSX-related events, but abnormalities are more sporadic and do not correlate well with the prognosis and response to therapy. Currently, targeted therapy for synovial sarcoma includes a limited range of drugs, and surgical resection is the mainstay treatment for localized cancer with adjuvant or neoadjuvant chemotherapy and radiotherapy. Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies. [ABSTRACT FROM AUTHOR]

Summary The chromosomal translocation t(1;6)(p35.3;p25.2) is a rare but recurrent aberration in chronic lymphocytic leukaemia (CLL). We report molecular characterization of 10 cases and show that this translocation juxtaposes interferon regulatory factor 4 (IRF4) on 6p25 with regulator of chromosome condensation 1 (RCC1) on 1p35. The breakpoints fell within the 5′ untranslated regions of both genes, resulting in RCC1::IRF4 fusion transcripts without alterations of the protein‐coding sequences. Levels of expression of both RCC1 and IRF4 proteins were not obviously deregulated. The cases showed other mutations typical of CLL and we confirm previously reported skewing towards the IGHV‐unmutated subtype. RCC1::IRF4 fusion characterizes a rare subset of CLL. [ABSTRACT FROM AUTHOR]

The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases and is a crucial protein in its development. Many studies have explored the role of FUS::DDIT3 in MLS, and the prevailing view is that FUS::DDIT3 inhibits adipocyte differentiation and promotes MLS growth and invasive migration by functioning as an aberrant transcription factor that affects gene expression and regulates its downstream molecules. As fusion proteins are gradually showing their potential as targets for precision cancer therapy, FUS::DDIT3 has also been investigated as a therapeutic target. Drugs that target FUS::DDIT3 and its downstream molecules for treating MLS are widely utilized in both clinical practice and experimental studies, and some of them have demonstrated promising results. This article reviews the findings of relevant research, providing an overview of the oncogenic mechanisms of the FUS::DDIT3 fusion protein in MLS, as well as recent advancements in its therapy. [ABSTRACT FROM AUTHOR]

Background: In this report, we describe an uncommon instance of fungating synovial sarcoma affecting the posterior aspect of the neck. Although the existing literature has documented a limited number of cases, this particular case contributes to the knowledge about it, which is scarce. Case presentation: A total of 5 months before the examination, a Pakistani-Asian male, age 20 years, complained of a malodorous fungating swelling on the posterior aspect of his neck. An examination revealed a foul-smelling, 10 × 13 cm fungating enlargement surrounded by maggots and hemorrhaging at the site of the incision. A hemoglobin level of 6 and a total leukocyte count (TLC) of 23,000 indicated the patient's disoriented and pallid appearance. He was expeditiously admitted, and preoperatively, the general well-being of the patient was optimized. After a comprehensive discussion with the medical team, a strategy for marginal excision and coverage with a latissimus dorsi (LD) flap and grafting was devised. The tumor was successfully excised, and an LD flap with graft was conducted on the patient during surgery; however, the infection caused the failure of half of the graft. Following that, the lesion was debrided, and re-grafting was performed. The patient was subsequently administered 5 cycles of chemotherapy and 32 cycles of radiotherapy. He was diagnosed with pulmonary metastasis 2 years later. Sadly, the patient died during a follow-up visit 3.5 years later. Conclusions: The patient's unfavorable prognosis after surgical intervention, radiotherapy, and chemotherapy, despite undergoing all-encompassing treatments, underscores the importance of early detection and intervention in fungating tumor cases. [ABSTRACT FROM AUTHOR]

Species delineation in microorganisms is challenging due to the limited markers available for accurate species assignment. Here, we applied an integrative taxonomy approach, combining extensive sampling, whole-genome sequence-based classification, phenotypic profiling, and assessment of interspecific reproductive isolation. Our work reveals the presence of a distinct Saccharomyces lineage in Nothofagus forests of coastal Patagonia. This lineage, designated Saccharomyces chiloensis sp. nov., exhibits 7% genetic divergence from its sister species S. uvarum, as revealed by whole-genome sequencing and population analyses. The South America-C (SA-C) coastal Patagonia population forms a unique clade closely related to a previously described divergent S. uvarum population from Oceania (AUS, found in Australia and New Zealand). Our species reclassification is supported by a low Ortho Average Nucleotide Identity (OANI) of 93% in SA-C and AUS relative to S. uvarum, which falls below the suggested species delineation threshold of 95%, indicating an independent evolutionary lineage. Hybrid spore viability assessment provided compelling evidence that SA-C and AUS are reproductively isolated from S. uvarum. In addition, we found unique structural variants between S. chiloensis sp. nov. lineages, including large-scale chromosomal translocations and inversions, together with a distinct phenotypic profile, emphasizing their intraspecies genetic distinctiveness. We suggest that S. chiloensis sp. nov diverged from S. uvarum in allopatry due to glaciation, followed by post-glacial dispersal, resulting in distinct lineages on opposite sides of the Pacific Ocean. The discovery of S. chiloensis sp. nov. illustrates the uniqueness of Patagonia's coastal biodiversity and underscores the importance of adopting an integrative taxonomic approach in species delineation to unveil cryptic microbial species. The holotype of S. chiloensis sp. nov. is CBS 18620T. Author summary: Author summary Species delineation in microorganisms is challenging due to limited genetic markers and the genetic complexity of reproductive isolation. In this study, we employed an integrative taxonomy approach, combining whole-genome sequencing, phenotypic profiling, and reproductive isolation assessments, to identify Saccharomyces chiloensis sp. nov., as a new yeast species isolated from the Nothofagus forests of Coastal Patagonia. This novel species exhibits significant genetic divergence from S. uvarum and shows unique structural variants that emphasize its distinct evolutionary lineage. Furthermore, isolates belonging to this species can also be found in Australia and New Zealand, which are genetically and phenotypically different from those isolated in Patagonia. The discovery of S. chiloensis sp. nov. highlights Patagonia's biodiversity's importance and the necessity of comprehensive taxonomic approaches to reveal cryptic species in microorganisms. Our findings have broader implications for understanding yeast diversity and the evolutionary processes shaping microbial species. [ABSTRACT FROM AUTHOR]

Unintended on-target chromosomal alterations induced by CRISPR/Cas9 in mammalian cells are common, particularly large deletions and chromosomal translocations, and present a safety challenge for genome editing. Thus, there is still an unmet need to develop safer and more efficient editing tools. We screened diverse DNA polymerases of distinct origins and identified a T4 DNA polymerase derived from phage T4 that strongly prevents undesired on-target damage while increasing the proportion of precise 1- to 2-base-pair insertions generated during CRISPR/Cas9 editing (termed CasPlus). CasPlus induced substantially fewer on-target large deletions while increasing the efficiency of correcting common frameshift mutations in DMD and restored higher level of dystrophin expression than Cas9-alone in human cardiomyocytes. Moreover, CasPlus greatly reduced the frequency of on-target large deletions during mouse germline editing. In multiplexed guide RNAs mediating gene editing, CasPlus repressed chromosomal translocations while maintaining gene disruption efficiency that was higher or comparable to Cas9 in primary human T cells. Therefore, CasPlus offers a safer and more efficient gene editing strategy to treat pathogenic variants or to introduce genetic modifications in human applications. Synopsis: While off-target mutations have been carefully addressed, CRISPR/Cas9 mediated genome editing often causes harmful on-target chromosomal alterations. CasPlus combines Cas9 genome editing with an engineered phage T4 DNA polymerase and reduces the incidence of large deletions and chromosomal translocations. CasPlus can be applied to correct disease-causing mutations such as in Duchenne muscular dystrophy (DMD), but also for generating engineered T cells for cell therapy. CasPlus editing inhibits undesired on-target large deletions while increasing the proportion of precise 1- to 2-base-pair insertions generated during CRISPR/Cas9 editing. CasPlus efficiently corrects the frameshift mutations in DMD (exon 52 deletions) with fewer on-target DNA damage. CasPlus greatly reduces the frequency of on-target large deletions in mouse germline editing. CasPlus represses chromosomal translocation while maintaining gene disruption efficiency that is higher or comparable to Cas9 in multiplex gene-edited human primary T cells. CasPlus combines Cas9 genome editing with an engineered phage T4 DNA polymerase and reduces the incidence of large deletions and chromosomal translocations. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background In this report, we describe an uncommon instance of fungating synovial sarcoma affecting the posterior aspect of the neck. Although the existing literature has documented a limited number of cases, this particular case contributes to the knowledge about it, which is scarce. Case presentation A total of 5 months before the examination, a Pakistani-Asian male, age 20 years, complained of a malodorous fungating swelling on the posterior aspect of his neck. An examination revealed a foul-smelling, 10 × 13 cm fungating enlargement surrounded by maggots and hemorrhaging at the site of the incision. A hemoglobin level of 6 and a total leukocyte count (TLC) of 23,000 indicated the patient’s disoriented and pallid appearance. He was expeditiously admitted, and preoperatively, the general well-being of the patient was optimized. After a comprehensive discussion with the medical team, a strategy for marginal excision and coverage with a latissimus dorsi (LD) flap and grafting was devised. The tumor was successfully excised, and an LD flap with graft was conducted on the patient during surgery; however, the infection caused the failure of half of the graft. Following that, the lesion was debrided, and re-grafting was performed. The patient was subsequently administered 5 cycles of chemotherapy and 32 cycles of radiotherapy. He was diagnosed with pulmonary metastasis 2 years later. Sadly, the patient died during a follow-up visit 3.5 years later. Conclusions The patient’s unfavorable prognosis after surgical intervention, radiotherapy, and chemotherapy, despite undergoing all-encompassing treatments, underscores the importance of early detection and intervention in fungating tumor cases.

Aberrant gene expression patterns in acute myeloid leukemia (AML) with balanced chromosomal translocations are often associated with dysregulation of epigenetic modifiers. The AML1/ETO (RUNX1/MTG8) fusion protein, caused by the translocation (8;21)(q22;q22), leads to the epigenetic repression of its target genes. We aimed in this work to identify critical epigenetic modifiers, on which AML1/ETO‐positive AML cells depend on for proliferation and survival using shRNA library screens and global transcriptomics approaches. Using shRNA library screens, we identified 41 commonly depleted genes in two AML1/ETO‐positive cell lines Kasumi‐1 and SKNO‐1. We validated, genetically and pharmacologically, DNMT1 and ATR using several AML1/ETO‐positive and negative cell lines. We also demonstrated in vivo differentiation of myeloblasts after treatment with the DNMT1 inhibitor decitabine in a patient with an AML1/ETO‐positive AML. Bioinformatic analysis of global transcriptomics after AML1/ETO induction in 9/14/18‐U937 cells identified 973 differentially expressed genes (DEGs). Three genes (PARP2, PRKCD, and SMARCA4) were both downregulated after AML1/ETO induction, and identified in shRNA screens. In conclusion, using unbiased shRNA library screens and global transcriptomics, we have identified several driver epigenetic regulators for proliferation in AML1/ETO‐positive AML. DNMT1 and ATR were validated and are susceptible to pharmacological inhibition by small molecules showing promising preclinical and clinical efficacy. [ABSTRACT FROM AUTHOR]

Chromosome structural variations (SVs), such as deletion, duplication, inversion, and translocation, are important contributors to genetic diversification and crop improvement. Using genome editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated nuclease (Cas9), desired SVs involving large DNA fragments have been created in rice (Oryza sativa L.), maize (Zea mays L.), and Arabidopsis (Arabidopsis thaliana L.). However, it is still uncertain whether the size of DNA fragment involved could be a prohibiting factor to generate Cas9‐mediated SVs. In this study, we constructed five CRISPR/Cas9 vectors, each expressing two single‐guide RNAs (sgRNAs), to cut two sites spacing at 0.5, 5, 10, 20, and 30 Mb on rice chromosome 4 (Chr4), respectively. Meanwhile, another CRISPR/Cas9 vector cutting two sites, one on Chr4 and the other on Chr1, was also constructed for creation of chromosomal translocation between Chr1 and Chr4. These vectors were transfected into rice protoplasts by polyethylene glycol–mediated transformation. Specific primers were designed to detect desired SV events. The results showed that all designed SVs could be effectively generated by CRISPR/Cas9 in rice protoplasts. This study suggested that the size of DNA fragment involved is unlikely a prohibiting factor for creation of desired SV events. [ABSTRACT FROM AUTHOR]

When an increased nuchal translucency (>3.00 mm) is observed during the echographic examination of a foetus in the first trimester of pregnancy, an increased risk of chromosomopathy is considered, and the pregnant woman is offered the possibility of an invasive investigation. Here, we focused our attention on prenatal diagnosis issues in cases of foetuses with cytogenetically balanced reciprocal translocations. We report the finding of a cytogenetically balanced, de facto genomically unbalanced translocation that poses a challenge in a case of prenatal diagnosis, changing the risk of Down syndrome in a Zellweger syndromic spectrum risk (PEX3 deletion). At term, a healthy baby was born. This case teaches that prenatal diagnosis in cases of foetuses at increased risk of chromosomal abnormality imperatively requires molecular investigation in addition to a morphological karyotype. [ABSTRACT FROM AUTHOR]

The management of chronic myeloid leukemia in the chronic phase (CML-CP) has witnessed significant advancements since the identification of a common chromosomal translocation anomaly involving chromosomes 9 and 22, which results in the formation of the Philadelphia chromosome driven by the BCR-ABL1 fusion protein. This discovery paved the way for the development of tyrosine kinase inhibitors (TKIs) that target the adenosine triphosphate (ATP) binding site of ABL1 through the BCR-ABL-1 fusion protein. Following the approval of Imatinib by the Food and Drug Administration (FDA) as the first TKI for CML treatment in 2001, the median overall survival (OS) for chronic phase CML (CML-CP) has significantly improved, approaching that of the general population. However, achieving this milestone crucially depends on reaching certain treatment response milestones. Since the introduction of imatinib, five additional TKIs have been approved for CML-CP treatment. Despite the availability of these treatments, many patients may experience treatment failure and require multiple lines of therapy due to factors such as the emergence of resistance, such as mutations in the ATP binding site of ABL, or intolerance to therapy. This review will primarily focus on exploring treatment options for patients who fail second-generation TKI therapy due to true resistance. [ABSTRACT FROM AUTHOR]

Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR–ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR–ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR–ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR–ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR–ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR–ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR–ABL1+ human ALL cell line, but had no effect on the BCR–ABL1− 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR–ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL. [ABSTRACT FROM AUTHOR]

Discovery and verification of diagnostic or therapeutic biomarkers for biliary tract cancer (BTC) is challenging owing to the low prevalence of the disease. Here, we identified and investigated the clinical impact of a fusion gene, Pumilio1-tumor necrosis factor receptor-associated factor 3 (PUM1-TRAF3), caused by 1;14 chromosomal translocation in BTC. PUM1-TRAF3 was initially identified in the RNA-sequencing of five BTC surgical tissues and confirmed by fluorescence in situ hybridization. Expression of the fusion gene was validated in an expanded cohort (5/55, 9.1%). Establishment and molecular assessment of PUM1-TRAF3 expressing BTC cells revealed that PUM1-TRAF3 activates non-canonical NF-κB signaling via NF-κB-inducing kinase (NIK). Abnormal TRAF3 activity, driven by competitive binding of PUM1-TRAF3 and TRAF3 to NIK, led to NIK rescue followed by P52/RelB nuclear translocation, all of which were reverted by an NIK inhibitor. The elevated expression of NIK and activated NF-κB signaling was observed in the PUM1-TRAF3-expressing regions of patient tissues. Expression of the PUM1-TRAF3 fusion was significantly correlated with strong NIK expression, which is associated with a poorer prognosis for patients with BTC. Overall, our study identifies a new fusion gene, PUM1-TRAF3, that activates NIK and non-canonical NF-κB signaling, which may be beneficial for developing precise treatment strategies for BTC. [ABSTRACT FROM AUTHOR]

A multiple-parameter based approach using radiation-induced clinical signs and symptoms, hematology changes, cytogenetic chromosomal aberrations, and molecular biomarkers changes after radiation exposure is used for biodosimetry-based dose assessment. In the current article, relevant milestones from Radiation Research are documented that forms the basis of the current consensus approach for diagnostics after radiation exposure. For example, in 1962 the use of cytogenetic chromosomal aberration using the lymphocyte metaphase spread dicentric assay for biodosimetry applications was first published in Radiation Research. This assay is now complimented using other cytogenetic chromosomal aberration assays (i.e., chromosomal translocations, cytokinesis-blocked micronuclei, premature chromosome condensation, γ-H2AX foci, etc.). Changes in blood cell counts represent an early-phase biomarker for radiation exposures. Molecular biomarker changes have evolved to include panels of organ-specific plasma proteomic and blood-based gene expression biomarkers for radiation dose assessment. Maturation of these assays are shown by efforts for automated processing and scoring, development of point-of-care diagnostics devices, service laboratories inter-comparison exercises, and applications for dose and injury assessments in radiation accidents. An alternative and complementary approach has been advocated with the focus to de-emphasize "dose" and instead focus on predicting acute or delayed health effects. The same biomarkers used for dose estimation (e.g., lymphocyte counts) can be used to directly predict the later developing severity degree of acute health effects without performing dose estimation as an additional or intermediate step. This review illustrates contributing steps toward these developments published in Radiation Research. [ABSTRACT FROM AUTHOR]

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons' DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Mesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation. Case presentation: We present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced "de novo" reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints. Conclusions: The identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1. [ABSTRACT FROM AUTHOR]

Background: B-cell acute lymphoblastic leukemia (B-ALL) is a complex disorder that includes multiple genetic changes, one of the main causes of which is rare and common chromosomal translocations that lead to abnormal gene fusions. This abnormal fusion produces a new protein that causes the leukemia cells. These types of rearrangements usually occur in lymphoma and result in the movement of genetic material between different chromosomes or within chromosomes. This systematic review aims to evaluate published studies and investigate the role and importance of common and rare chromosomal translocations in the occurrence of BALL. Material and Methods: This systematic review investigated and evaluated the evidence regarding the effect of chromosomal translocations in adults and pediatrics with B-ALL. This review was based on the preferred reporting items for systematic reviews and meta-analysis checklists. A literature search was conducted using international databases (such as PubMed, Web of Science, Scopus, Research Gate, Google Scholar, and Cochrane Systematic Reviews database). Only English-language articles published between January 2010 and January 2023 including MESH terms such as ALL, B-ALL, and chromosomal translocations were selected. Seventy-five related studies had the necessary criteria to be examined in the present study. Results: A total of 237 articles were retrieved in the online search. The excluded articles included research on other types of leukemia in adults and children, descriptive studies, case studies, studies related to animal models of leukemogenesis, and comparisons of common treatment methods of leukemia grouping cancers. Finally, seventy-five studies were identified as eligible for inclusion in this systematic review. Conclusion: This review provides a comprehensive assessment of common and rare chromosomal translocations that can lead to the development of cancer cells. Chromosomal translocations play a role as diagnostic markers and important prognostic indicators and help specialists adjust treatment approaches according to their occurrence. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) shows multiple chromosomal translocations & point mutations which can be used to refine risk-adapted therapy in AML patients. Ecotropic viral integration site-1 (EVI-1) & myocyte enhancer factor 2 C gene (MEF2C) are key regulatory transcription factors in hematopoiesis and leukemogenesis & both drive immune escape. This prospective study involved 80 adult de novo AML patients recruited from Oncology Center, Mansoura University, between March 2019 and July 2021. The MEF2C and EVI1 expression were measured using a Taqman probe-based qPCR assay. The results revealed that EVI1 and MEF2C expression were significantly elevated in AML patients as compared to control subjects (p = 0.001. 0.007 respectively). Aberrant expressions of EVI1 and MEF2C showed a significant negative correlation with hemoglobin levels (p = 0.034, 0.025 respectively), & bone marrow blasts (p = 0.007, 0.002 respectively). 11q23 translocation was significantly associated with EVI1 and MEF2C (p = 0.004 and 0.02 respectively). Also, t (9;22) was significantly associated with EVI1 and MEF2C (p = 0.01 and 0.03 respectively), higher expression of EVI1 and MEF2C were significantly associated with inferior outcome after induction therapy (p = 0.001 and 0.018 respectively) and shorter overall survival (p = 0.001, 0.014 respectively). In conclusion, EVI1 & MEF2C were significantly expressed in AML cases. EVI1 & MEF2C overexpression were significantly associated with 11q23 rearrangements and t (9;22) and were indicators for poor outcome in adult AML patients; These results could be a step towards personalized therapy in those patients. [ABSTRACT FROM AUTHOR]

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2−/−/Jak3−/− (BRJ) mice, it formed tumor masses within 4–6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK. [ABSTRACT FROM AUTHOR]

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy. Tyrosine kinases are promising therapeutic targets in multiple cancer types; however, the formation and selection of tyrosine kinase fusions are not fully understood. Here, the authors develop a genome-wide fusion sequencing platform and identify mechanisms and patterns of fusion formation that have implication for targeted therapy. [ABSTRACT FROM AUTHOR]

Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression. Here, the authors identify a form of central iris hypoplasia affecting the pupillary zone. They suggest that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression. [ABSTRACT FROM AUTHOR]

While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions. [ABSTRACT FROM AUTHOR]

Chromosomal translocations can result in phenotypic effects of varying severity, depending on the position of the breakpoints and the rearrangement of genes within the interphase nucleus of the translocated chromosome regions. Balanced translocations are often asymptomatic phenotypically and are typically detected due to a decrease in fertility resulting from issues during meiosis. Robertsonian translocations are among the most common chromosomal abnormalities, often asymptomatic, and can persist in the population as a normal polymorphism. We serendipitously discovered a Robertsonian translocation between chromosome 21 and chromosome 22, which is inherited across three generations without any phenotypic effect, notably only in females. In situ hybridization with alpha-satellite DNAs revealed the presence of both centromeric sequences in the translocated chromosome. The reciprocal translocation resulted in a partial deletion of the short arm of both chromosomes 21, and 22, with the ribosomal RNA genes remaining present in the middle part of the new metacentric chromosome. The rearrangement did not cause alterations to the long arm. The spread of an asymptomatic heterozygous chromosomal polymorphism in a population can lead to mating between heterozygous individuals, potentially resulting in offspring with a homozygous chromosomal configuration for the anomaly they carry. This new karyotype may not produce phenotypic effects in the individual who presents it. The frequency of karyotypes with chromosomal rearrangements in asymptomatic heterozygous form in human populations is likely underestimated, and molecular karyotype by array Comparative Genomic Hybridization (array-CGH) analysis does not allow for the identification of this type of chromosomal anomaly, making classical cytogenetic analysis the preferred method for obtaining clear results on a karyotype carrying a balanced rearrangement. [ABSTRACT FROM AUTHOR]

Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1 , wherein the karyotype revealed t(2; 2 ;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21). [ABSTRACT FROM AUTHOR]

Jayne et al. provide a molecular characterization of the t(1;6)(p35.3;p25.2) chromosomal translocation in patients with chronic lymphocytic leukaemia. They indicate that this translocation involves the gene encoding interferon regulatory factor 4 (IRF4) on chromosome 6p25.2 with the regulator of chromosome condensation 1 (RCC1) gene on chromosome 1p35.3. This translocations may have important prognostic value.Commentary on: Jayne et al. The chromosomal translocation t(1;6)(p35.3;p25.2), recurrent in chronic lymphocytic leukaemia leads to RCC1::IRF4 fusion. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19790. [ABSTRACT FROM AUTHOR]

The article discusses the potential for a breakthrough in the treatment of chronic myeloid leukemia (CML) with a new drug called asciminib. The drug targets a specific genetic mutation associated with CML and has shown promising results in clinical trials. While current treatments for CML have improved survival rates, many patients still require lifelong or long-term therapies. Asciminib offers the possibility of treatment discontinuation and improved long-term safety. However, further research is needed to fully understand its effects and compare it to existing treatments. In another article, the role of exceptional individuals with unique genetic traits in the development of medicines for coronary artery disease is explored. The discovery of the PCSK9 gene as a therapeutic target for coronary artery disease has led to the development of pharmacologic inhibitors. Genetic studies have identified individuals with loss-of-function variants in PCSK9, resulting in lower LDL cholesterol levels and a reduced incidence of coronary artery disease. These findings have paved the way for the development of targeted therapies for cardiovascular diseases. [Extracted from the article]

FGFR3-TACC3 represents an oncogenic fusion protein frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Various exon breakpoints of FGFR3-TACC3 have been identified in cancers; these were analyzed to determine the minimum contribution of TACC3 for activation of the FGFR3-TACC3 fusion protein. While TACC3 exons 11 and 12 are dispensable for activity, our results show that FGFR3-TACC3 requires exons 13-16 for biological activity. A detailed analysis of exon 13, which consists of 8 heptads forming a coiled coil, further defined the minimal region for biological activity as consisting of 5 heptads from exon 13, in addition to exons 14-16. These conclusions were supported by transformation assays of biological activity, examination of MAPK pathway activation, analysis of disulfide-bonded FGFR3-TACC3, and by examination of the Endoglycosidase H-resistant portion of FGFR3-TACC3. These results demonstrate that clinically identified FGFR3-TACC3 fusion proteins differ in their biological activity, depending upon the specific breakpoint. This study further suggests the TACC3 dimerization domain of FGFR3-TACC3 as a novel target in treating FGFR translocation driven cancers.

Objective: The objective of this study is to investigate the factors that influence the live birth rate (LBR) of the first single euploid frozen-thawed blastocyst transfer (FBT) cycles after preimplantation genetic testing for structural rearrangements (PGT-SR) in couples with balanced chromosomal translocations (BCT). Design: Single center, retrospective and observational study. Methods: A total of 336 PGT-SR and the first single euploid FBT cycles between July 2016 and December 2022 were included in this study. The patients were divided into two groups according to the live birth outcomes. The parameters of the study population, controlled ovarian stimulation cycles, and FBT cycles were analyzed. Multivariable binary logistic regression was performed to find the factors that affected the LBR. Results: The percentage of blastocysts at developmental stage Day 5 compared to Day 6 (51.8% vs. 30.8%; P<0.001) and with morphology =BB compared to

The phenomenon of de novo gene birth—the emergence of genes from non-genic sequences—has received considerable attention due to the widespread occurrence of genes that are unique to particular species or genomes. Most instances of de novo gene birth have been recognized through comparative analyses of genome sequences in eukaryotes, despite the abundance of novel, lineage-specific genes in bacteria and the relative ease with which bacteria can be studied in an experimental context. Here, we explore the genetic record of the Escherichia coli long-term evolution experiment (LTEE) for changes indicative of "proto-genic" phases of new gene birth in which non-genic sequences evolve stable transcription and/or translation. Over the time span of the LTEE, non-genic regions are frequently transcribed, translated and differentially expressed, with levels of transcription across low-expressed regions increasing in later generations of the experiment. Proto-genes formed downstream of new mutations result either from insertion element activity or chromosomal translocations that fused preexisting regulatory sequences to regions that were not expressed in the LTEE ancestor. Additionally, we identified instances of proto-gene emergence in which a previously unexpressed sequence was transcribed after formation of an upstream promoter, although such cases were rare compared to those caused by recruitment of preexisting promoters. Tracing the origin of the causative mutations, we discovered that most occurred early in the history of the LTEE, often within the first 20,000 generations, and became fixed soon after emergence. Our findings show that proto-genes emerge frequently within evolving populations, can persist stably, and can serve as potential substrates for new gene formation. De novo gene birth from non-genic sequence has received considerable attention due to the widespread occurrence of genes that are unique to particular species. This study shows that within the short evolutionary timescale of the iconic E. coli LTEE experiment, the co-option of promoters, principally from transposable elements, serves as the major source of raw material for new genes. [ABSTRACT FROM AUTHOR]

Tethering of a key mutagenic enzyme (activation-induced deaminase, AID) to RNA emanating from RNA polymerase provides insights into its physiological and pathological action. We propose a model where tethering of AID to nascent RNA is important for its action at translocation fragile zones ranging from 20 to 600 bp in size. Tethering likely supports the targeting of AID during its normal function in immunoglobulin class switch recombination and somatic hypermutation. Broader roles of tethering by the enzymes of the APOBEC family may be relevant to APOBEC functions in antiviral defense and other responses to cell stress. One of the two chromosomal breakage events in recurring translocations in B cell neoplasms is often due to the recombination-activating gene complex (RAG complex) releasing DNA ends before end joining. The other break occurs in a fragile zone of 20–600 bp in a non-antigen receptor gene locus, with a more complex and intriguing set of mechanistic factors underlying such narrow fragile zones. These factors include activation-induced deaminase (AID), which acts only at regions of single-stranded DNA (ssDNA). Recent work leads to a model involving the tethering of AID to the nascent RNA as it emerges from the RNA polymerase. This mechanism may have relevance in class switch recombination (CSR) and somatic hypermutation (SHM), as well as broader relevance for other DNA enzymes. [ABSTRACT FROM AUTHOR]

Background/Aim: Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS). Materials and Methods: Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing. Results: We identified a balanced t(17;19)(q21;p13) translocation in both siblings' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein. Conclusion: The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood. [ABSTRACT FROM AUTHOR]

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect a disease-associated chromosomal translocation between 17p13 and the 19 centromere. We constructed two sets of phased and non-phased de novo assemblies; (i) based on lrGS only and (ii) hybrid assemblies combining lrGS with optical mapping using lrGS reads with a median coverage of 34X. Variant calling detected both structural variants (SVs) and small variants and the accuracy of the small variant calling was compared with those called with short-read genome sequencing (srGS). The de novo and hybrid assemblies had high quality and contiguity with N50 of 62.85 Mb, enabling a near telomere to telomere assembly with less than a 100 contigs per haplotype. Notably, we successfully identified the centromeric breakpoint of the translocation. A concordance of 92% was observed when comparing small variant calling between srGS and lrGS. In summary, our findings underscore the remarkable potential of lrGS as a comprehensive and accurate solution for the analysis of SVs and small variants. Thus, lrGS could replace a large battery of genetic tests that were used for the diagnosis of a single symptomatic translocation carrier, highlighting the potential of lrGS in the realm of digital karyotyping. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML. [ABSTRACT FROM AUTHOR]

The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs) could be due to the magnified downstream effects initiated by a smaller group of genomic higher-order alterations in response to endogenous or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with microRNAs, gene copy number variants (CNVs), sub-microscopic deletions and duplications of DNA, rare single-nucleotide variants (SNVs/SNPs), and small insertions/deletions (indels), as well as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon activity, and 3-D chromosomal topology characteristics. These genomic structural features have been linked with various NPDs in mostly isolated reports and have usually only been viewed as areas harboring potential candidate genes of interest. The suggestion to use a higher level entry point (the 'fragilome' and associated features) activated by a central mechanism ('stress') for studying NPD genetics has the potential to unify the existing vast number of different observations in this field. This approach may explain the continuum of gene findings distributed between affected and unaffected individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical and molecular heterogeneity, and the association with certain other medical disorders. [ABSTRACT FROM AUTHOR]

Y chromosomes are thought to undergo progressive degeneration due to stepwise loss of recombination and subsequent reduction in selection efficiency. However, the timescales and evolutionary forces driving degeneration remain unclear. To investigate the evolution of sex chromosomes on multiple timescales, we generated a high-quality phased genome assembly of the massive older (<10 MYA) and neo (<200,000 yr) sex chromosomes in the XYY cytotype of the dioecious plant Rumex hastatulus and a hermaphroditic outgroup Rumex salicifolius. Our assemblies, supported by fluorescence in situ hybridization, confirmed that the neo-sex chromosomes were formed by two key events: an X-autosome fusion and a reciprocal translocation between the homologous autosome and the Y chromosome. The enormous sex-linked regions of the X (296 Mb) and two Y chromosomes (503 Mb) both evolved from large repeat-rich genomic regions with low recombination; however, the complete loss of recombination on the Y still led to over 30% gene loss and major rearrangements. In the older sex-linked region, there has been a significant increase in transposable element abundance, even into and near genes. In the neo-sex-linked regions, we observed evidence of extensive rearrangements without gene degeneration and loss. Overall, we inferred significant degeneration during the first 10 million years of Y chromosome evolution but not on very short timescales. Our results indicate that even when sex chromosomes emerge from repetitive regions of already-low recombination, the complete loss of recombination on the Y chromosome still leads to a substantial increase in repetitive element content and gene degeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: The Spanish cattle breeds "Berrenda en Colorado" and "Berrenda en Negro" are considered endangered breeds. For years, breeders' associations have been implementing breeding strategies in herds to address the presence of the Robertsonian translocation (rob (1;29)), which is a disease that causes a decline in reproductive performance. Single-nucleotide polymorphism (SNP) genotyping detection techniques are presented as an appropriate means to evaluate genetic diversity. However, previous research on genetic variability in both breeds has been carried out using DNA microsatellites. Therefore, we studied the genetic diversity, population structure, and potential genetic differences among individuals of both Berrenda breeds and groups based on the presence of the Robertsonian chromosomal translocation, rob (1;29). The genetic diversity in terms of expected heterozygosity was significantly lower in those subpopulations containing rob (1;29) within the breed, but in general, the four subpopulations considered showed minor genetic differences. The presence of this Robertsonian translocation did not result in sub-structuring associated with this chromosomal disorder within either of the breeds. The improvement of the reproductive performance of the Berrenda breeds requires the implementation of breeding strategies based on the contributions to the populations of the breeding stock carrying rob (1;29). Most of the previous studies on the genetic variability in Spanish "Berrenda" breeds have been carried out using DNA microsatellites. The present work aimed to estimate the genetic diversity, population structure, and potential genetic differences among individuals of both Berrenda breeds and groups based on the presence of the Robertsonian chromosomal translocation, rob (1;29). A total of 373 samples from animals belonging to the two breeds, including 169 cases diagnosed as rob (1;29)-positive, were genotyped using an SNP50K chip. The genetic diversity at the breed level did not show significant differences, but it was significantly lower in those subpopulations containing the rob (1;29). Runs of homozygosity identified a region of homozygosity on chromosome 6, where the KIT (KIT proto-oncogene, receptor tyrosine kinase) gene, which determines the typical spotted coat pattern in both breeds, is located. The four subpopulations considered showed minor genetic differences. The regions of the genome that most determined the differences between the breeds were observed on chromosomes 4, 6, 18, and 22. The presence of this Robertsonian translocation did not result in sub-structuring within each of the breeds considered. To improve the reproductive performance of Berrenda breeds, it would be necessary to implement strategies considering the involvement of potential breeding stock carrying rob (1;29). [ABSTRACT FROM AUTHOR]

Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-β). This overexpression of TGF-β1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-β also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-β in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future. [ABSTRACT FROM AUTHOR]

Chromosome analysis (CA) and chromosomal microarray analysis (CMA) have been successfully used to diagnose genetic disorders. However, many conditions remain undiagnosed due to limitations in resolution (CA) and detection of only unbalanced events (CMA). Optical genome mapping (OGM) has the potential to address these limitations by capturing both structural variants (SVs) resulting in copy number changes and balanced rearrangements with high resolution. In this study, we investigated OGM's concordance using 87 SVs previously identified by CA, CMA, or Southern blot. Overall, OGM was 98% concordant with only three discordant cases: (1) uncalled translocation with one breakpoint in a centromere; (2) uncalled duplication with breakpoints in the pseudoautosomal region 1; and (3) uncalled mosaic triplication originating from a marker chromosome. OGM provided diagnosis for three previously unsolved cases: (1) disruption of the SON gene due to a balanced reciprocal translocation; (2) disruption of the NBEA gene due to an inverted insertion; (3) disruption of the TSC2 gene due to a mosaic deletion. We show that OGM is a valid method for the detection of many types of SVs in a single assay and is highly concordant with legacy cytogenomic methods; however, it has limited SV detection capabilities in centromeric and pseudoautosomal regions. [ABSTRACT FROM AUTHOR]

Purpose: This review primarily aims to review the epidemiology, clinical characteristics, imaging, pathology, immunohistochemistry, diagnosis, differential diagnosis, treatment, and prognosis of Primary pulmonary myxoid sarcoma (PPMS) with EWS RNA binding protein 1::cAMP response element binding protein 1 (EWSR1::CREB1) fusion. It provides reference for the diagnosis and treatment of this disease. Methods: Retrospectively collected the literature about PPMS with EWSR1::CREB1 fusion, its clinical, radiology, histology, molecular characteristics and current treatment strategies were collated and analyzed. This review provides a detailed differential diagnosis of the disease. Results: PPMS is an exceptionally rare, low-grade malignant tumor of the lung. This tumor commonly infiltrates lung tissue and develops within bronchial passages. It is identified by a genetic rearrangement involving the EWSR1 gene and a distinct chromosomal translocation t(2; 22)(q33; q12). Variants include EWSR1::CREB1 fusion and EWS RNA binding protein 1::activating transcription factors (EWSR1::ATF1) fusion. PPMS with EWSR1::CREB1 fusion is more prevalent among middle-aged individuals and affects both sexes almost equally. Clinical symptoms are relatively non-specific, primarily including cough, hemoptysis, and weight loss. Most patients undergo surgery and experience a favorable prognosis. Further research is required to validate the effectiveness of alternative treatments for PPMS with EWSR1::CREB1 fusion. Conclusion: EWSR1 rearrangement and EWSR1::CREB1 fusion are crucial genetic features of PPMS and serve as important diagnostic markers. Immunohistochemically, PPMS tests positive for EMA. In terms of treatment, surgery has been the primary approach in recent years. Therefore, the efficacy of other treatments still requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Genome manipulation of Leishmania species and the creation of modified strains are widely employed strategies for various purposes, including gene function studies, the development of live attenuated vaccines, and the engineering of host cells for protein production. Objective: Despite the introduction of novel manipulation approaches like CRISPR/Cas9 technology with significant advancements in recent years, the development of a reliable protocol for efficiently and precisely altering the genes of Leishmania strains remains a challenging endeavor. Following the successful adaptation of the CRISPR/Cas9 system for higher eukaryotic cells, several research groups have endeavored to apply this system to manipulate the genome of Leishmania. Results: Despite the substantial differences between Leishmania and higher eukaryotes, the CRISPR/Cas9 system has been effectively tested and applied in Leishmania. Conclusion: This comprehensive review summarizes all the CRISPR/Cas9 systems that have been employed in Leishmania, providing details on their methods and the expression systems for Cas9 and gRNA. The review also explores the various applications of the CRISPR system in Leishmania, including the deletion of multicopy gene families, the development of the Leishmania vaccine, complete gene deletions, investigations into chromosomal translocations, protein tagging, gene replacement, large-scale gene knockout, genome editing through cytosine base replacement, and its innovative use in the detection of Leishmania. In addition, the review offers an up-to-date overview of all double-strand break repair mechanisms in Leishmania. [ABSTRACT FROM AUTHOR]

The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases and is a crucial protein in its development. Many studies have explored the role of FUS::DDIT3 in MLS, and the prevailing view is that FUS::DDIT3 inhibits adipocyte differentiation and promotes MLS growth and invasive migration by functioning as an aberrant transcription factor that affects gene expression and regulates its downstream molecules. As fusion proteins are gradually showing their potential as targets for precision cancer therapy, FUS::DDIT3 has also been investigated as a therapeutic target. Drugs that target FUS::DDIT3 and its downstream molecules for treating MLS are widely utilized in both clinical practice and experimental studies, and some of them have demonstrated promising results. This article reviews the findings of relevant research, providing an overview of the oncogenic mechanisms of the FUS::DDIT3 fusion protein in MLS, as well as recent advancements in its therapy.

Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. However, other genetic and epigenetic abnormalities in SS do not necessarily include SS18-SSX-related events, but abnormalities are more sporadic and do not correlate well with the prognosis and response to therapy. Currently, targeted therapy for synovial sarcoma includes a limited range of drugs, and surgical resection is the mainstay treatment for localized cancer with adjuvant or neoadjuvant chemotherapy and radiotherapy. Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.

Pre-B cell leukemia factor 1 (PBX1) is a Three Aminoacid Loop Extension (TALE) homeodomain-containing transcription factor playing crucial roles in organ pattering during embryogenesis, through the formation of nuclear complexes with other TALE class and/or homeobox proteins to regulate target genes. Its contribution to the development of several organs has been elucidated mainly through the study of murine knockout models. A crucial role for human development has been recently highlighted through the discovery of different de novo pathogenic PBX1 variants in children affected by developmental defects. In the adult, PBX1 is expressed in selected tissues such as in the brain, in the gastro-intestinal and urinary systems, or in hematopoietic stem and progenitor cells, while in other organs is barely detectable. When involved in the t(1;19) chromosomal translocation it acts as an oncogene, since the resulting fusion protein drives pre-B cell leukemia, due to the induction of target genes not normally targeted by the native protein. Its aberrant expression has been associated to tumor development, progression, or therapy-resistance as in breast cancer, ovarian cancer or myeloproliferative neoplasm (MPN). On the other hand, in colorectal cancer PBX1 functions as a tumor suppressor, highlighting its context-dependent role. We here discuss differences and analogies of PBX1 roles during embryonic development and in cancer, focusing mainly on the most recent discoveries. [ABSTRACT FROM AUTHOR]

Chromosomal rearrangements have been shown to alter genome organization, consequently having an impact on gene expression. Studies on certain types of leukemia have shown that gene expression can be exacerbated by the altered nuclear positioning of fusion genes arising from chromosomal translocations. However, studies on lymphoma have been, so far, very limited. The scope of this study was to explore genome organization in lymphoma cells carrying the t(14;18)(q32;q21) rearrangement known to results in over-expression of the BCL2 gene. In order to achieve this aim, we used fluorescence in situ hybridization to carefully map the positioning of whole chromosome territories and individual genes involved in translocation in the lymphoma-derived cell line Pfeiffer. Our data show that, although there is no obvious alteration in the positioning of the whole chromosome territories, the translocated genes may take the nuclear positioning of either of the wild-type genes. Furthermore, the BCL2 gene was looping out in a proportion of nuclei with the t(14;18) translocation but not in control nuclei without the translocation, indicating that chromosome looping may be an essential mechanism for BCL2 expression in lymphoma cells. [ABSTRACT FROM AUTHOR]

Microdeletion syndromes are genetic diseases caused by multilocus chromosomal deletions too small to be detected by karyotyping. They are typified by complex pleiotropic developmental phenotypes that depend both on the extent of the deletion and variations in genetic background. Microdeletion alleles cause a wide array of consequences involving multiple pathways. How simultaneous haploinsufficiency of numerous adjacent genes leads to complex and variable pleiotropic phenotypes is not well understood. CRISPR/Cas9 genome editing has been shown to induce microdeletion-like alleles at a meaningful rate. Here, we describe a microdeletion allele in Caenorhabditis elegans recovered during a CRISPR/Cas9 genome editing experiment. We mapped the allele to chromosome V, balanced it with a reciprocal translocation crossover suppressor, and precisely defined the breakpoint junction. The allele simultaneously removes 32 protein-coding genes, yet animals homozygous for this mutation are viable as adults. Homozygous animals display a complex phenotype including maternal effect lethality, producing polynucleated embryos that grow into uterine tumors, vulva morphogenesis defects, body wall distensions, uncoordinated movement, and a shortened life span typified by death by bursting. Our work provides an opportunity to explore the complexity and penetrance of microdeletion phenotypes in a simple genetic model system. [ABSTRACT FROM AUTHOR]

Protein kinases function as pivotal regulators in biological events, governing essential cellular processes through the transfer of phosphate groups from ATP molecules to substrates. Dysregulation of kinase activity is frequently associated with cancer, ocasionally arising from chromosomal translocation events that relocate genes encoding kinases. Fusion proteins resulting from such events, particularly those involving the proto-oncogene tyrosine-protein kinase ROS (ROS1), manifest as constitutively active kinases, emphasizing their role in oncogenesis. Notably, the chromosomal reallocation of the ros1 gene leads to fusion of proteins with the ROS1 kinase domain, implicated in various cancer types. Despite their prevalence, targeted inhibition of these fusion proteins relies on repurposed kinase inhibitors. This review comprehensively surveys experimentally determined ROS1 structures, emphasizing the pivotal role of X-ray crystallography in providing high-quality insights. We delve into the intricate interactions between ROS1 and kinase inhibitors, shedding light on the structural basis for inhibition. Additionally, we explore point mutations identified in patients, employing molecular modeling to elucidate their structural impact on the ROS1 kinase domain. By integrating structural insights with in vitro and in silico data, this review advances our understanding of ROS1 kinase in cancer, offering potential avenues for targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Summary: Spontaneous chromosomal rearrangements (CRs) play an essential role in speciation, genome evolution and crop domestication. To be able to use the potential of CRs for breeding, plant chromosome engineering was initiated by fragmenting chromosomes by X‐ray irradiation. With the rise of the CRISPR/Cas system, it became possible to induce double‐strand breaks (DSBs) in a highly efficient manner at will at any chromosomal position. This has enabled a completely new level of predesigned chromosome engineering. The genetic linkage between specific genes can be broken by inducing chromosomal translocations. Natural inversions, which suppress genetic exchange, can be reverted for breeding. In addition, various approaches for constructing minichromosomes by downsizing regular standard A or supernumerary B chromosomes, which could serve as future vectors in plant biotechnology, have been developed. Recently, a functional synthetic centromere could be constructed. Also, different ways of genome haploidization have been set up, some based on centromere manipulations. In the future, we expect to see even more complex rearrangements, which can be combined with previously developed engineering technologies such as recombinases. Chromosome engineering might help to redefine genetic linkage groups, change the number of chromosomes, stack beneficial genes on mini cargo chromosomes, or set up genetic isolation to avoid outcrossing. [ABSTRACT FROM AUTHOR]