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PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗
PubMed2005

Genome-assisted analysis of dissimilatory metal-reducing bacteria.

The availability of whole genome sequences for Shewanella oneidensis and Geobacter sulfurreducens has provided numerous new biological insights into the function of these model dissimilatory metal-reducing bacteria. Many of these findings, including the identification of a high number of c-type cytochromes in both organisms, have resulted from comparative genomic analyses, and several have been experimentally confirmed. These genome sequences have also aided the identification of genes important for the reduction of metal ions and other electron acceptors utilized during anaerobic growth, by facilitating the identification of genes disrupted by random insertions. Technologies for assaying global expression patterns for genes and proteins have also been employed, but their application has been limited mainly to the analysis of the role of global regulatory genes and to identifying genes expressed or repressed in response to specific electron acceptors. It is anticipated that details of the mechanisms of metal ion respiration, and metabolism in general, will eventually be revealed by comprehensive, systems-level analyses enabled by functional genomics data.

Bacterial Proteins↗
PubMed2002

A transcription factor response element for gene expression during circadian night.

Mammalian circadian clocks consist of complex integrated feedback loops that cannot be elucidated without comprehensive measurement of system dynamics and determination of network structures. To dissect such a complicated system, we took a systems-biological approach based on genomic, molecular and cell biological techniques. We profiled suprachiasmatic nuclei and liver genome-wide expression patterns under light/dark cycles and constant darkness. We determined transcription start sites of human orthologues for newly identified cycling genes and then performed bioinformatical searches for relationships between time-of-day specific expression and transcription factor response elements around transcription start sites. Here we demonstrate the role of the Rev-ErbA/ROR response element in gene expression during circadian night, which is in phase with Bmal1 and in antiphase to Per2 oscillations. This role was verified using an in vitro validation system, in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence.

Animals↗
PubMed2026

Immune pathway activation in gastric cancers with LINE-1 retrotransposon overexpression and homologous recombination deficiency.

There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.

Journal Article↗
PubMed2005

Development of oncology drug response markers using transcription profiling.

Transcriptional profiling of a tumor's entire genomic complement has become a key tool in the analysis of human cancers and identification of novel markers to predict disease state, outcome, and response to therapy. At present, this technology provides the most comprehensive approach for the analysis of somatic changes altering critical pathways during transformation of stable diploid cells into unstable tumor cells. Such analyses are impacting the development of novel anti-cancer drugs through the early detection of cancer, development of targeted therapies, identification of optimal dose and regimens for new drugs, and segmentation of patients to enrich response rates and reduce risk of adverse events.

Antineoplastic Agents↗
PubMed2026

Comprehensive profiling of antibiotic resistance genes and functional clusters of orthologous groups annotation of gut microbiota in Indonesian Kedu chickens.

Antibiotic resistance is a growing global health concern, with poultry systems acting as important reservoirs of antibiotic resistance genes (ARGs). However, resistome and functional profiles of indigenous chickens raised under traditional systems remain underexplored. This study aimed to characterize the antibiotic resistome, virulence factor genes, and metabolic potential of gut microbiota in Indonesian Kedu chickens using a shotgun metagenomic approach. Digesta samples from five gastrointestinal segments of 21 healthy adult chickens were analyzed through high-throughput sequencing. ARGs were identified using the Comprehensive Antibiotic Resistance Database (CARD) and Antibiotic Resistance Genes Databases (ARDB), while virulence factors and functional genes were annotated using Virulence Factor Database (VFDB), Clusters of Orthologous Groups (COG), and Carbohydrate-Active EnZymes (CAZy) databases. Results revealed a diverse resistome dominated by multidrug resistance and efflux pump mechanisms, with prominent genes associated with fluoroquinolone, tetracycline, β-lactam, and glycopeptide resistance. The detection of clinically relevant ARGs suggests that genetic determinants associated with antimicrobial resistance are present in the gut microbiota of traditionally raised Kedu chickens, although metagenomic data alone cannot determine whether these genes are actively expressed or confer phenotypic resistance. Virulence factor analysis showed functions related to adherence, immune evasion, iron acquisition, quorum sensing, and efflux activity, reflecting strong microbial adaptability. Functional profiling demonstrated enrichment in translation, carbohydrate and amino acid metabolism, genome maintenance, and cell envelope biogenesis. Additionally, CAZyme analysis indicated a high capacity for complex polysaccharide degradation, supporting efficient utilization of fiber-rich traditional diets. In conclusion, this study provides a comprehensive metagenomic overview of antibiotic resistance and functional potential in Kedu chicken gut microbiota, emphasizing the importance of incorporating indigenous poultry into antimicrobial resistance surveillance within a One Health framework.

Antibiotic resistance genes↗
PubMed2002

Domain-oriented functional analysis based on expression profiling.

BACKGROUND: Co-regulation of genes may imply involvement in similar biological processes or related function. Many clusters of co-regulated genes have been identified using microarray experiments. In this study, we examined co-regulated gene families using large-scale cDNA microarray experiments on the human transcriptome. RESULTS: We present a simple model, which, for each probe pair, distills expression changes into binary digits and summarizes the expression of multiple members of a gene family as the Family Regulation Ratio. The set of Family Regulation Ratios for each protein family across multiple experiments is called a Family Regulation Profile. We analyzed these Family Regulation Profiles using Pearson Correlation Coefficients and derived a network diagram portraying relationships between the Family Regulation Profiles of gene families that are well represented on the microarrays. Our strategy was cross-validated with two randomly chosen data subsets and was proven to be a reliable approach. CONCLUSION: This work will help us to understand and identify the functional relationships between gene families and the regulatory pathways in which each family is involved. Concepts presented here may be useful for objective clustering of protein functions and deriving a comprehensive protein interaction map. Functional genomic approaches such as this may also be applicable to the elucidation of complex genetic regulatory networks.

Amino Acid Sequence↗
PubMed2005

Ability to differentiate between cp and ncp BVDV by microarrays: towards an application in clinical veterinary medicine?

Microarray expression profiling provides a comprehensive portrait of the transcriptional world enabling us to view the organism as a 'system' that is more than the sum of its parts. The vigilance of cells to environmental change, the alacrity of the transcriptional response, the short half-life of cellular mRNA and the genome-scale nature of the investigation collectively explain the power of this method. These same features pose the most significant experimental design and execution issues which, unless surmounted, predictably generate a distorted image of the transcriptome. Conversely, the expression profile of a properly conceived and conducted microarray experiment can be used for hypothesis testing: disclosure of the metabolic and biosynthetic pathways that underlie adaptation of the organism to infectious processes; the identification of co-ordinately regulated genes; the regulatory circuits and signal transduction systems that mediate the adaptive response; and temporal features of developmental programmes. The study of viral pathogenesis by microarray expression profiling poses special challenges and opportunities. Although the technical hurdles are many, obtaining expression profiles of an organism growing in tissue will probably reveal strategies for growth and survival of the virus in the host's cells. Here, we show data obtained using a tailored microarray system based on synthetic polynucleotides derived from human sequences (SIRS-Lab GmbH, Jena, Germany) to study the effect of cytopathogenic (cpe) and non-cytopathogenic (ncp) bovine viral diarrhoea virus (BVDV) infection of bovine macrophages, focusing on intracellular signalling molecules. Of the 575 genes present on the array, more than 70% showed a reaction with the oligonuleotides spotted on the array, and 26 genes were differentially expressed comparing cDNA derived from cpe and ncp infected cells. These data will help to further understand our knowledge regarding BVDV infection, and will especially help to understand differences in cellular responses to cpe and ncp biotypes.

Animals↗
PubMed2005

Aberrant DNA methylation as a cancer-inducing mechanism.

Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16(INK4a), BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation "invades" the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.

Animals↗
PubMed2006

An integrated strategy for analyzing the unique developmental programs of different myoblast subtypes.

An important but largely unmet challenge in understanding the mechanisms that govern the formation of specific organs is to decipher the complex and dynamic genetic programs exhibited by the diversity of cell types within the tissue of interest. Here, we use an integrated genetic, genomic, and computational strategy to comprehensively determine the molecular identities of distinct myoblast subpopulations within the Drosophila embryonic mesoderm at the time that cell fates are initially specified. A compendium of gene expression profiles was generated for primary mesodermal cells purified by flow cytometry from appropriately staged wild-type embryos and from 12 genotypes in which myogenesis was selectively and predictably perturbed. A statistical meta-analysis of these pooled datasets--based on expected trends in gene expression and on the relative contribution of each genotype to the detection of known muscle genes--provisionally assigned hundreds of differentially expressed genes to particular myoblast subtypes. Whole embryo in situ hybridizations were then used to validate the majority of these predictions, thereby enabling true-positive detection rates to be estimated for the microarray data. This combined analysis reveals that myoblasts exhibit much greater gene expression heterogeneity and overall complexity than was previously appreciated. Moreover, it implicates the involvement of large numbers of uncharacterized, differentially expressed genes in myogenic specification and subsequent morphogenesis. These findings also underscore a requirement for considerable regulatory specificity for generating diverse myoblast identities. Finally, to illustrate how the developmental functions of newly identified myoblast genes can be efficiently surveyed, a rapid RNA interference assay that can be scored in living embryos was developed and applied to selected genes. This integrated strategy for examining embryonic gene expression and function provides a substantially expanded framework for further studies of this model developmental system.

Animals↗
PubMedDate not supplied

Relevant genomics of neurotensin receptor in cancer.

The expressed sequence tag (EST) databases are an attractive starting point for gene discovery for diseases like cancer. Validation of gene targets from these sequences (both known and novel) in cancers requires a comprehensive expression profiling. We identified from the Cancer Gene Anatomy Project database (CGAP), a hit called neurotensin receptor (NT-r) that was expressed in the pancreatic cancer cDNA libraries. Neurotensin (NT), a neuroendocrine peptide, exerts trophic effects in vivo and stimulates the growth of cancer-derived cell lines in vitro. High affinity neurotensin receptors (NT-r) are expressed in cancer-derived cell lines and in some primary tumors. To date, a comprehensive expression profile of the NT-r in diverse cancers and normal tissues has not been reported. A cancer-selective expression of NT-r, if demonstrable, may provide a basis for a diagnostic and potential therapeutic utility. We demonstrate that the NT-r is expressed in a variety of cancer-derived cell lines as well as primary tumors, but only in a select few normal tissues. The expression of NT, on the other hand, was detected in many normal tissues, but not in the cancer-derived cell lines. The NT expression however, was detected in the primary tumors. We further demonstrate that NT expression is stimulated by androgen deprivation in the prostate cancer models. These results demonstrate the usefulness of a panel of cDNA repository for rapid validation of potential cancer targets.

Breast Neoplasms↗
PubMed2026

An Aspergillus luchuensis isolated from a patient with hemoptysis insights from a comprehensive genome-based analysis: Case report.

RATIONALE: Asp luchuensis, a member of the A niger group, is widely used in food fermentation and rarely causes invasive pulmonary aspergillosis (IPA) in humans. Clinical cases of IPA induced by this strain are extremely scarce, and its genomic characteristics, virulence profiles, and pathogenic mechanisms remain poorly understood, resulting in insufficient clinical recognition of its invasive infection potential. PATIENT CONCERNS: A 57-year-old immunocompetent non-neutropenic male patient with a long-term smoking and drinking history presented with unexplained severe cough and massive hemoptysis (approximately100 mL) without other typical infectious symptoms. DIAGNOSES: Combined with chest computed tomography (CT) inflammatory lesions, positive galactomannan test, fungal PCR and metagenomic next-generation sequencing results, the patient was definitively diagnosed with probable A luchuensis-induced IPA. Genomic and transcriptomic analyses confirmed the pathogen as a variant A luchuensis strain with 3 key hypervirulence genes, highly active mitochondrial energy metabolism, and no specific antifungal resistance genes. INTERVENTIONS: The patient received standardized intravenous antifungal combination therapy with voriconazole and amphotericin B after confirmed diagnosis. OUTCOMES: The patient's cough and hemoptysis were significantly relieved after 10 days of treatment, with stable vital signs and no adverse drug reactions or disease progression. LESSONS: A luchuensis possesses strong invasive pathogenicity and can trigger IPA even in non-neutropenic immunocompetent individuals. Negative conventional microbial tests cannot exclude its infection, and mNGS is a reliable diagnostic tool. This strain is susceptible to routine antifungal drugs, and clinicians should raise awareness of atypical Asp species-induced invasive pulmonary infections.

Humans↗
PubMed2003

Chromatin remodeling as a guide to transcriptional regulatory networks in mammals.

An important challenge of genome biology is a dissection of transcriptional regulatory networks that operate inside the nucleus during ontogeny and disease (Wyrick and Young [2002] Curr. Opin. Genet. Dev. 12:130). Limitations of existing experimental tools greatly complicate such analysis in the human genome: for example, genome-wide expression profiling of cells responding to a stimulus fails to reveal a majority of the genes involved in the functional network of responding to that stimulus [Giaver et al., 2002; Birrell et al., 2002]. This article discusses recent advances in analyzing mammalian transcriptional regulatory circuits [Nikiforov et al., 2002; Weinmann et al., 2002; Ren et al., 2000]. As evidenced by these and other data, paucity of information about the location of regulatory DNA elements in the human genome presents an obstacle to comprehensive transcription network analysis. It has been known since the late 1970s that chromatin over active regulatory DNA stretches is stably remodeled into "nuclease hypersensitive sites" [Elgin, 1988; Gross and Garrard 1988]. Massively parallel analysis of such remodeling in cell nuclei identifies regulatory DNA that is difficult to map comprehensively using other approaches, reveals genes poised for rapid activation, and offers a novel perspective on the "epigenome"--the regulatory program being executed by the genome in a given cell type.

Animals↗
PubMed2002

Mutation profiling of mismatch repair-deficient colorectal cncers using an in silico genome scan to identify coding microsatellites.

Human colorectal, endometrial, and gastric cancers with defective DNA mismatch repair (MMR) have microsatellite instability, a unique molecular alteration characterized by widespread frameshift mutations of repetitive DNA sequences. We developed "Kangaroo," a bioinformatics program for searches in nucleotide and protein sequence databases, and performed an in silico genome scan for DNA coding microsatellites that may have novel mutations in MMR-deficient cancers. Examination of 29 previously untested coding polyadenines revealed widespread mutations in MMR-deficient colorectal cancers, with the highest frequencies in ERCC5, CASP8AP2, p72, RAD50, CDC25, RECQL1, CBF2, RACK7, GRK4, and DNAPK (range, 10-33%). This algorithm allows comprehensive mutation profiling of MMR-deficient cancers, an important step in understanding the pathogenesis of these neoplasms.

Algorithms↗
PubMed2001

Chemical inhibition of the Pho85 cyclin-dependent kinase reveals a role in the environmental stress response.

In addition to its well-established role in responding to phosphate starvation, the cyclin-dependent kinase Pho85 has been implicated in a number of other physiological responses of the budding yeast Saccharomyces cerevisiae, including synthesis of glycogen. To comprehensively characterize the range of Pho85-dependent gene expression, we used a chemical genetic approach that enabled us to control Pho85 kinase activity with a cell-permeable inhibitor and whole genome transcript profiling. We found significant phenotypic differences between the rapid loss of activity caused by inhibition and the deletion of the genomic copy of PHO85. We demonstrate that Pho85 controls the expression of not only previously identified glycogen synthetic genes, but also a significant regulon of genes involved in the cellular response to environmental stress. In addition, we show that the effects of this inhibitor are both rapid and reversible, making it well suited to the study of the behavior of dynamic signaling pathways.

Alleles↗
PubMed2006

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Adult↗