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Cancer Cell Dec 2019Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded...
Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Chromatin; Gene Expression Regulation, Leukemic; Gene Rearrangement; Humans; Leukemia, Myeloid, Acute; Mice; Proto-Oncogene Proteins; Transcription Factors
PubMed: 31821784
DOI: 10.1016/j.ccell.2019.11.001 -
Medicine Jun 2020To investigate the gene rearrangement and mutation of lymphoma biomarkers including (Immunoglobulin H (IgH), Immunoglobulin kappa (IGK), Immunoglobulin lambda (IGL), and...
INTRODUCTION
To investigate the gene rearrangement and mutation of lymphoma biomarkers including (Immunoglobulin H (IgH), Immunoglobulin kappa (IGK), Immunoglobulin lambda (IGL), and TCR) in the lymphoma diagnosis.
METHODS AND ANALYSIS
Paraffin tissue samples from 240 cases diagnosed as suspected lymphoma in the department of pathology, Deyang City People's Hospital from June 2020 to June 2021 will be enrolled. Deoxyribonucleic acid extraction and Polymerase Chain Reaction (PCR) amplification will be performed in these paraffin tissue samples. Immunoglobulin and T cell receptor (TCR) rearrangement will be analyzed by hetero-double chain gel electrophoresis and BioMed-2 standardized immunoglobulin gene rearrangement detection system. In this study protocol IGH gene rearrangement, IGK gene rearrangement, both IGH and IGL gene rearrangement, both IGH and IGK gene rearrangement, both IGK and IGL gene rearrangement, both IGH, IGK and IGL gene rearrangement, TCR gene rearrangement and positive Ig/TCR rearrangement will be analyzed.
DISCUSSION
In this study, we will use B and T cell lymphoma analysis focusing on IgH, IGK, IGL, and TCR gene rearrangement, so as to provide early guidance for the diagnosis of lymphoma. Second generation sequencing technology is helpful in the differential diagnosis of lymphoma.
TRIAL REGISTRATION
Chinese Clinical trial registry: ChiCTR2000032366.
Topics: Gene Rearrangement; Humans; Lymphoma; Mutation; Observational Studies as Topic; Prospective Studies; Research Design
PubMed: 32541525
DOI: 10.1097/MD.0000000000020733 -
Disease Models & Mechanisms Sep 2021The identification of large chromosomal rearrangements in cancers has multiplied exponentially over the last decade. These complex and often rare genomic events have... (Review)
Review
The identification of large chromosomal rearrangements in cancers has multiplied exponentially over the last decade. These complex and often rare genomic events have traditionally been challenging to study, in part owing to lack of tools that efficiently engineer disease-associated inversions, deletions and translocations in model systems. The emergence and refinement of genome editing technologies, such as CRISPR, have significantly expanded our ability to generate and interrogate chromosomal aberrations to better understand the networks that govern cancer growth. Here we review how existing technologies are employed to faithfully model cancer-associated chromosome rearrangements in the laboratory, with the ultimate goal of developing more accurate pre-clinical models of and therapeutic strategies for cancers driven by these genomic events.
Topics: Chromosome Aberrations; Chromosomes; Gene Editing; Gene Rearrangement; Genome; Humans; Neoplasms
PubMed: 34585724
DOI: 10.1242/dmm.049078 -
Cellular and Molecular Life Sciences :... Nov 2020Ciliates are a highly divergent group of unicellular eukaryotes with separate somatic and germline genomes found in distinct dimorphic nuclei. This characteristic... (Review)
Review
Ciliates are a highly divergent group of unicellular eukaryotes with separate somatic and germline genomes found in distinct dimorphic nuclei. This characteristic feature is tightly linked to extremely laborious developmentally regulated genome rearrangements in the development of a new somatic genome/nuclei following sex. The transformation from germline to soma genome involves massive DNA elimination mediated by non-coding RNAs, chromosome fragmentation, as well as DNA amplification. In this review, we discuss the similarities and differences in the genome reorganization processes of the model ciliates Paramecium and Tetrahymena (class Oligohymenophorea), and the distantly related Euplotes, Stylonychia, and Oxytricha (class Spirotrichea).
Topics: Animals; Cell Nucleus; Ciliophora; Gene Rearrangement; Genome, Protozoan; Germ Cells; Humans
PubMed: 32462406
DOI: 10.1007/s00018-020-03555-2 -
Bulletin of Mathematical Biology Sep 2023Early literature on genome rearrangement modelling views the problem of computing evolutionary distances as an inherently combinatorial one. In particular, attention is...
Early literature on genome rearrangement modelling views the problem of computing evolutionary distances as an inherently combinatorial one. In particular, attention is given to estimating distances using the minimum number of events required to transform one genome into another. In hindsight, this approach is analogous to early methods for inferring phylogenetic trees from DNA sequences such as maximum parsimony-both are motivated by the principle that the true distance minimises evolutionary change, and both are effective if this principle is a true reflection of reality. Recent literature considers genome rearrangement under statistical models, continuing this parallel with DNA-based methods, with the goal of using model-based methods (for example maximum likelihood techniques) to compute distance estimates that incorporate the large number of rearrangement paths that can transform one genome into another. Crucially, this approach requires one to decide upon a set of feasible rearrangement events and, in this paper, we focus on characterising well-motivated models for signed, uni-chromosomal circular genomes, where the number of regions remains fixed. Since rearrangements are often mathematically described using permutations, we isolate the sets of permutations representing rearrangements that are biologically reasonable in this context, for example inversions and transpositions. We provide precise mathematical expressions for these rearrangements, and then describe them in terms of the set of cuts made in the genome when they are applied. We directly compare cuts to breakpoints, and use this concept to count the distinct rearrangement actions which apply a given number of cuts. Finally, we provide some examples of rearrangement models, and include a discussion of some questions that arise when defining plausible models.
Topics: Phylogeny; Gene Rearrangement; Mathematical Concepts; Models, Biological; Genome; Algorithms; Models, Genetic
PubMed: 37749280
DOI: 10.1007/s11538-023-01209-5 -
Cell Cycle (Georgetown, Tex.) 2015The application of Next-Generation Sequencing for studying the genetics of papillary thyroid carcinomas (PTC) has recently revealed new somatic mutations and gene... (Review)
Review
The application of Next-Generation Sequencing for studying the genetics of papillary thyroid carcinomas (PTC) has recently revealed new somatic mutations and gene fusions as potential new tumor-initiating events in patients without any known driver lesion. Gene and miRNA expression analyses defined clinically relevant subclasses correlated to tumor progression. In addition, it has been shown that tumor driver mutations in BRAF, and RET rearrangements - altogether termed "BRAF-like" carcinomas - have a very similar expression pattern and constitute a distinct category. Conversely, "RAS-like" carcinomas have a different genomic, epigenomic, and proteomic profile. These findings justify the need to reconsider PTC classification schemes.
Topics: Animals; Carcinoma; Carcinoma, Papillary; Gene Rearrangement; Humans; Mutation; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 26030480
DOI: 10.1080/15384101.2015.1049786 -
Methods in Molecular Biology (Clifton,... 2022Identification of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements in acute lymphoblastic leukemia (ALL) patients at initial presentation are crucial for...
Identification of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements in acute lymphoblastic leukemia (ALL) patients at initial presentation are crucial for monitoring of minimal residual disease (MRD) during subsequent follow-up and thereby for appropriate risk-group stratification. Here we describe how RNA-Seq data can be generated and subsequently analyzed with ARResT/Interrogate to identify possible MRD markers. In addition to the procedures, possible pitfalls will be discussed. Similar strategies can be employed for other lymphoid malignancies, such as lymphoma and myeloma.
Topics: Aftercare; Gene Rearrangement; Genes, T-Cell Receptor; Humans; Immunoglobulins; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA-Seq; Risk Assessment
PubMed: 35622320
DOI: 10.1007/978-1-0716-2115-8_4 -
Scientific Reports Jan 2022The genus Anastatus comprises a large group of parasitoids, including several biological control agents in agricultural and forest systems. The taxonomy and phylogeny of...
The genus Anastatus comprises a large group of parasitoids, including several biological control agents in agricultural and forest systems. The taxonomy and phylogeny of these species remain controversial. In this study, the mitogenome of A. fulloi Sheng and Wang was sequenced and characterized. The nearly full-length mitogenome of A. fulloi was 15,692 bp, compromising 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes and a control region (CR). The total A + T contents were 83.83%, 82.18%, 87.58%, 87.27%, and 82.13% in the whole mitogenome, 13 PCGs, 22 tRNA genes, 2 rRNA genes, and CR, respectively. The mitogenome presented negative AT skews and positive GC skews, except for the CR. Most PCGs were encoded on the heavy strand, started with ATN codons, and ended with TAA codons. Among the 3736 amino acid-encoding codons, TTA (Leu1), CGA (Arg), TCA (Ser2), and TCT (Ser2) were predominant. Most tRNAs had cloverleaf secondary structures, except trnS1, with the absence of a dihydrouridine (DHU) arm. Compared with mitogenomes of the ancestral insect and another parasitoid within Eupelmidae, large-scale rearrangements were found in the mitogenome of A. fulloi, especially inversions and inverse transpositions of tRNA genes. The gene arrangements of parasitoid mitogenomes within Chalcidoidea were variable. A novel gene arrangement was presented in the mitogenome of A. fulloi. Phylogenetic analyses based on the 13 protein-coding genes of 20 parasitoids indicated that the phylogenetic relationship of 6 superfamilies could be presented as Mymaridae + (Eupelmidae + (Encyrtidae + (Trichogrammatidae + (Pteromalidae + Eulophidae)))). This study presents the first mitogenome of the Anastatus genus and offers insights into the identification, taxonomy, and phylogeny of these parasitoids.
Topics: Animals; Gene Rearrangement; Hymenoptera; RNA, Ribosomal; RNA, Transfer
PubMed: 35079090
DOI: 10.1038/s41598-022-05419-0 -
International Journal of Molecular... Mar 2022Chromoanagenesis constitutes a group of events that arise from single cellular events during early development. This particular class of complex rearrangements is a... (Review)
Review
Chromoanagenesis constitutes a group of events that arise from single cellular events during early development. This particular class of complex rearrangements is a newfound occurrence that may lead to chaotic and complex genomic realignments. By that, chromoanagenesis is thought to be a crucial factor regarding macroevolution of the genome, and consequently is affecting the karyotype revolution together with genomic plasticity. One of chromoanagenesis-type of events is chromothripsis. It is characterised by the breakage of the chromosomal structure and its reassembling in random order and orientation which results in the establishment of derivative forms of chromosomes. Molecular mechanisms that underlie this phenomenon are mostly related to chromosomal sequestration throughout the micronuclei formation process. Chromothripsis is linked both to congenital and cancer diseases, moreover, it might be detected in subjects characterised by a normal phenotype. Chromothripsis, as well as the other chromoanagenetic variations, may be confined to one or more chromosomes, which makes up a non-uniform variety of karyotypes among chromothriptic patients. The detection of chromothripsis is enabled via tools like microarray-based comparative genomic hybridisation, next generation sequencing or authorial protocols aimed for the recognition of structural variations.
Topics: Chromothripsis; Comparative Genomic Hybridization; Gene Rearrangement; Genome; Genomics; Humans
PubMed: 35328739
DOI: 10.3390/ijms23063318 -
International Journal of Molecular... Sep 2020, a small benthic fish, belongs to the Cynoglossidae, Pleuronectiformes. It was rarely studied due to its low abundance and cryptical lifestyle. In order to understand...
, a small benthic fish, belongs to the Cynoglossidae, Pleuronectiformes. It was rarely studied due to its low abundance and cryptical lifestyle. In order to understand the mitochondrial genome and the phylogeny in Cynoglossidae, the complete mitogenome of has been sequenced and analyzed for the first time. The total length is 16,425 bp, typically containing 37 genes with novel gene rearrangements. The tRNA- gene is inverted from the light to the heavy strand and translocated from the downstream of tRNA- gene to its upstream. The control region (CR) translocated downstream to the 3'-end of gene adjoining to inverted to tRNA- and left a 24 bp trace fragment in the original position. The phylogenetic trees were reconstructed by Bayesian inference (BI) and maximum likelihood (ML) methods based on the mitogenomic data of 32 tonguefish species and two outgroups. The results support the idea that Cynoglossidae is a monophyletic group and indicate that has the closest phylogenetic relationship with . By combining fossil records and mitogenome data, the time-calibrated evolutionary tree of families Cynoglossidae and Soleidae was firstly presented, and it was indicated that Cynoglossidae and Soleidae were differentiated from each other during Paleogene, and the evolutionary process of family Cynoglossidae covered the Quaternary, Neogene and Paleogene periods.
Topics: Animals; DNA, Mitochondrial; Evolution, Molecular; Flatfishes; Gene Rearrangement; Genome, Mitochondrial; Phylogeny
PubMed: 32962212
DOI: 10.3390/ijms21186895