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Leukemia May 2024The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL)....
The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.
Topics: Animals; Mice; Disease Models, Animal; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Aneuploidy; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Centrosome; Diploidy
PubMed: 38519798
DOI: 10.1038/s41375-024-02221-x -
Scientific Reports Mar 2024Hydatidiform moles are abnormal conceptuses. Many hydatidiform moles are diploid androgenetic, and of these, most are homozygous in all loci. Additionally, most...
Hydatidiform moles are abnormal conceptuses. Many hydatidiform moles are diploid androgenetic, and of these, most are homozygous in all loci. Additionally, most hydatidiform moles are euploid. Using Single Nucleotide Polymorphism (SNP) array analysis, in two studies a higher frequency of aneuploidy was observed in diploid androgenetic heterozygous conceptuses, than in their homozygous counterparts. In the Danish Mole Project, we analyze conceptuses suspected to be hydatidiform moles due to the clinical presentation, using karyotyping and Short Tandem Repeat (STR) analysis. Among 278 diploid androgenetic conceptuses, 226 were homozygous in all loci and 52 (18.7%) were heterozygous in several loci. Among 142 triploid diandric conceptuses, 141 were heterozygous for paternally inherited alleles in several loci. Here we show that the frequencies of aneuploidy in diploid androgenetic heterozygous and triploid diandric heterozygous conceptuses were significantly higher than the frequency of aneuploidy in diploid androgenetic homozygous conceptuses. In diploid androgenetic and triploid diandric conceptuses that are heterozygous for paternally inherited alleles, the two paternally inherited sets of genomes originate in two spermatozoa. Each spermatozoon provides one pair of centrioles to the zygote. The presence of two pairs of centrioles may cause an increased risk of aneuploidy.
Topics: Male; Pregnancy; Female; Humans; Diploidy; Triploidy; Hydatidiform Mole; Heterozygote; Aneuploidy; Uterine Neoplasms
PubMed: 38519579
DOI: 10.1038/s41598-024-57465-5 -
scRNA-seq Reveals Novel Genetic Pathways and Sex Chromosome Regulation in Tribolium Spermatogenesis.Genome Biology and Evolution Mar 2024Spermatogenesis is critical to sexual reproduction yet evolves rapidly in many organisms. High-throughput single-cell transcriptomics promises unparalleled insight into...
Spermatogenesis is critical to sexual reproduction yet evolves rapidly in many organisms. High-throughput single-cell transcriptomics promises unparalleled insight into this important process but understanding can be impeded in nonmodel systems by a lack of known genes that can reliably demarcate biologically meaningful cell populations. Tribolium castaneum, the red flour beetle, lacks known markers for spermatogenesis found in insect species like Drosophila melanogaster. Using single-cell sequencing data collected from adult beetle testes, we implement a strategy for elucidating biologically meaningful cell populations by using transient expression stage identification markers, weighted principal component clustering, and SNP-based haploid/diploid phasing. We identify populations that correspond to observable points in sperm differentiation and find species specific markers for each stage. Our results indicate that molecular pathways underlying spermatogenesis in Coleoptera are substantially diverged from those in Diptera. We also show that most genes on the X chromosome experience meiotic sex chromosome inactivation. Temporal expression of Drosophila MSL complex homologs coupled with spatial analysis of potential chromatin entry sites further suggests that the dosage compensation machinery may mediate escape from meiotic sex chromosome inactivation and postmeiotic reactivation of the X chromosome.
Topics: Animals; Male; Tribolium; Drosophila melanogaster; Single-Cell Gene Expression Analysis; Semen; Sex Chromosomes; Spermatogenesis; Drosophila; Coleoptera
PubMed: 38513111
DOI: 10.1093/gbe/evae059 -
Nature Communications Mar 2024Long-read sequencing offers long contiguous DNA fragments, facilitating diploid genome assembly and structural variant (SV) detection. Efficient and robust algorithms...
Long-read sequencing offers long contiguous DNA fragments, facilitating diploid genome assembly and structural variant (SV) detection. Efficient and robust algorithms for SV identification are crucial with increasing data availability. Alignment-based methods, favored for their computational efficiency and lower coverage requirements, are prominent. Alternative approaches, relying solely on available reads for de novo genome assembly and employing assembly-based tools for SV detection via comparison to a reference genome, demand significantly more computational resources. However, the lack of comprehensive benchmarking constrains our comprehension and hampers further algorithm development. Here we systematically compare 14 read alignment-based SV calling methods (including 4 deep learning-based methods and 1 hybrid method), and 4 assembly-based SV calling methods, alongside 4 upstream aligners and 7 assemblers. Assembly-based tools excel in detecting large SVs, especially insertions, and exhibit robustness to evaluation parameter changes and coverage fluctuations. Conversely, alignment-based tools demonstrate superior genotyping accuracy at low sequencing coverage (5-10×) and excel in detecting complex SVs, like translocations, inversions, and duplications. Our evaluation provides performance insights, highlighting the absence of a universally superior tool. We furnish guidelines across 31 criteria combinations, aiding users in selecting the most suitable tools for diverse scenarios and offering directions for further method development.
Topics: Humans; Sequence Analysis, DNA; Algorithms; Genome, Human; Diploidy; Benchmarking; High-Throughput Nucleotide Sequencing
PubMed: 38503752
DOI: 10.1038/s41467-024-46614-z -
BioRxiv : the Preprint Server For... Mar 2024Chromosomal aberrations are prevalent in cancer genomes, yet it remains challenging to resolve the long-range structure of rearranged chromosomes. A key problem is to...
Chromosomal aberrations are prevalent in cancer genomes, yet it remains challenging to resolve the long-range structure of rearranged chromosomes. A key problem is to determine the chromosomal origin of rearranged genomic segments, which requires chromosome-length haplotype information. Here we describe refLinker, a new computational method for whole-chromosome haplotype inference using external reference panels and Hi-C. We show that refLinker ensures consistent long-range phasing accuracy in both diploid human genomes and aneuploid cancers, including regions with loss-of-heterozygosity and high-level focal amplification. We further demonstrate the feasibility of complex genome reconstruction using haplotype-specific Hi-C contacts, revealing new karyotype features in two widely studied cancer cell lines. Together, these findings provide a new framework for the complete resolution of long-range chromosome structure in complex genomes and highlight the unique advantages of Hi-C data for reconstructing cancer genomes with chromosome-scale continuity.
PubMed: 38496539
DOI: 10.1101/2024.03.02.583108 -
Journal of Inflammation Research 2024Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy.
PURPOSE
Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy.
PATIENTS AND METHODS
In our study, we used both single-cell RNA sequencing (scRNA-seq) and bulk sequencing techniques to analyze MM patients. We analyzed each sample using gene set variation analysis (GSVA) based on immune-related gene sets. We also conducted further analyses to compare immune infiltration, clinical characteristics, and expression of immune checkpoint molecules between the H-S100A9 and L-S100A9 groups of MM patients.
RESULTS
We identified eight subpopulations of plasma cells, with S100A9 plasma cells being more abundant in patients with 1q21 gain and 1q21 diploid. CellChat analysis revealed that GAS and HGF signaling pathways were prominent in intercellular communication of S100A9 plasma cells. We identified 14 immune-related genes in the S100A9 plasma cell population, which allowed us to classify patients into the H-S100A9 group or the L-S100A9 group. The H-S100A9 group showed higher ESTIMATE, immune and stroma scores, lower tumor purity, and greater immune checkpoint expression. Patients with 1q21 gain and four or more copies had the lowest ESTIMATE score, immune score, stroma score, and highest tumor purity. Drug sensitivity analysis indicated that the H-S100A9 group had lower IC50 values and greater drug sensitivity compared to the L-S100A9 group. Quantitative reverse transcription (RT-q) PCR showed significantly elevated expression of RNASE6, LYZ, S100A8, S100A9, and S100A12 in MM patients compared to the healthy control group.
CONCLUSION
Our study has identified a correlation between molecular subtypes of S100A9 plasma cells and the response to immunotherapy in MM patients. These findings improve our understanding of tumor immunology and provide guidance for developing effective immunotherapy strategies for this patient population.
PubMed: 38481477
DOI: 10.2147/JIR.S452062 -
Clinical Infectious Diseases : An... Jun 2024A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial.
BACKGROUND
A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®).
METHODS
This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection.
RESULTS
Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines.
CONCLUSIONS
In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines.
CLINICAL TRIALS REGISTRATION
NCT03965962.
Topics: Humans; Rabies Vaccines; Adult; Male; Rabies; Post-Exposure Prophylaxis; Female; Antibodies, Viral; Double-Blind Method; Middle Aged; Young Adult; Vero Cells; Antibodies, Neutralizing; France; Rabies virus; Animals; Chlorocebus aethiops; Adolescent; Immunogenicity, Vaccine; Healthy Volunteers
PubMed: 38478634
DOI: 10.1093/cid/ciae137 -
International Journal of Molecular... Mar 2024The gene family plays a crucial role in regulating seed and organ size in plants. The gene family has been identified in several species but has not yet been reported...
The gene family plays a crucial role in regulating seed and organ size in plants. The gene family has been identified in several species but has not yet been reported in sweet potatoes. In this study, nine, eleven, and seven s were identified in cultivated sweet potato (, 2n = 6x = 90) and its two diploid wild relatives, (2n = 2x = 30) and (2n = 2x = 30), respectively. The genes were classified into three subgroups based on their phylogenetic relationships with and (rice). Their protein physiological properties, chromosomal localization, phylogenetic relationships, gene structure, promoter cis-elements, and expression patterns were systematically analyzed. The qRT-PCR results showed that the expression levels of four genes, , , , and , were higher in the sweet potato leaves than in the roots, fiber roots, and stems. In our study, we provide a comprehensive comparison and further the knowledge of genes in sweet potatoes, and provide a theoretical basis for functional studies.
Topics: Ipomoea batatas; Phylogeny; Diploidy; Genome, Plant; Genes, Plant; Gene Expression Regulation, Plant
PubMed: 38474246
DOI: 10.3390/ijms25053000 -
Molecular Genetics & Genomic Medicine Mar 2024Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by... (Review)
Review
BACKGROUND
Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by mutations of the RB1 gene or amplification of the MYCN gene. Rb may rarely present with polydactyly.
METHODS
We conducted karyotype analysis, copy number variation sequencing, and whole-genome sequencing on the infant proband and his family. The clinical course and laboratory results of the proband's infant were documented and collected. We also reviewed the relevant literature.
RESULTS
A 68-day-old boy presented with preaxial polydactyly and corneal edema. His intraocular pressure (IOP) was 40/19 mmHg, and color Doppler imaging revealed vitreous solid mass-occupying lesions with calcification in the right eye. Ocular CT showed flaky high-density and calcification in the right eye. This was classified as an International Retinoblastoma Staging System group E retinoblastoma with an indication for enucleation. Enucleation and orbital implantation were performed on the child's right eye. Karyotype analysis revealed an abnormal 46, XY, 15pstk+ karyotype, and the mother exhibited diploidy of the short arm of chromosome 15. The Alx-4 development factor, 13q deletion syndrome, and the PAPA2 gene have been reported as potential mechanisms for Rb combined with polydactyly.
CONCLUSION
We report the case of a baby boy with Rb and polydactyly exhibiting a 46, XY, 15pstk+ Karyotype. We discuss potential genetic factors related to both Rb and polydactyly. Furthermore, there is a need for further exploration into the impact of chromosomal polymorphisms in Rb with polydactyly.
Topics: Humans; Infant; Male; Calcinosis; DNA Copy Number Variations; Karyotype; Polydactyly; Retinal Neoplasms; Retinoblastoma
PubMed: 38465842
DOI: 10.1002/mgg3.2414