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PubMed2026

IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response.

Large-scale sequencing efforts have defined up to 27 diagnostic subtypes in B-cell precursor acute lymphoblastic leukemia (B-ALL), leaving few samples unclassified. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection, enabling identification of novel subtypes. We analyzed 4857 patients with B-ALL from 3 cohorts and identified a group of 20 patients (age, 18-66 years; median, 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n = 17/20), KRAS p.A146T/V/P mutations (n = 17/20 vs n = 86/4857; P< .001), and distinct DNA methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 (FOXF1/FENDRR) as well as JAK/STAT and RAS/MAPK signaling signatures. A gene expression machine learning classifier accurately identified FOXF1/FENDRR cases in 2 independent cohorts. Patients treated according to German Multicenter Study Group for Adult ALL (GMALL)/Group for Research in Adult ALL (GRAALL) protocols showed very poor chemotherapy response with 8 of 13 exhibiting induction failure or minimal residual disease (MRD) ≥10-3 and 8 of 12 remaining MRD positive after first consolidation/salvage. Intensification including blinatumomab (n = 10) and/or allogeneic stem cell transplantation (n = 12) resulted in ongoing molecular remission in 13 of 16 patients. FOXF1/FENDRR represents a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

Humans↗

PubMed2001

Complex signatures of natural selection at the Duffy blood group locus.

The Duffy blood group locus (FY) has long been considered a likely target of natural selection, because of the extreme pattern of geographic differentiation of its three major alleles (FY*B, FY*A, and FY*O). In the present study, we resequenced the FY region in samples of Hausa from Cameroon (fixed for FY*O), Han Chinese (fixed for FY*A), Italians, and Pakistanis. Our goals were to characterize the signature of directional selection on FY*O in sub-Saharan Africa and to understand the extent to which natural selection has also played a role in the extreme geographic differentiation of the other derived allele at this locus, FY*A. The data from the FY region are compared with the patterns of variation observed at 10 unlinked, putatively neutral loci from the same populations, as well as with theoretical expectations from the neutral-equilibrium model. The FY region in the Hausa shows evidence of directional selection in two independent properties of the data (i.e., level of sequence variation and frequency spectrum), observations that are consistent with the FY*O mutation being the target. The Italian and Chinese FY data show patterns of variation that are very unusual, particularly with regard to frequency spectrum and linkage disequilibrium, but do not fit the predictions of any simple model of selection. These patterns may represent a more complex and previously unrecognized signature of positive selection.

Alleles↗

PubMed1997

Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase.

For more than two-thirds of this century we have known that one of the most common and profound phenotypes of cancer cells is their propensity to utilize and catabolize glucose at high rates. This common biochemical signature of many cancers, particularly those that are poorly differentiated and proliferate rapidly, has remained until recently a "metabolic enigma." However, with many advances in the biological sciences having been applied to this problem, cancer cells have begun to reveal their molecular strategies in maintaining an aberrant metabolic behavior. Specifically, studies performed over the past two decades in our laboratory demonstrate that hexokinase, particularly the Type II isoform, plays a critical role in initiating and maintaining the high glucose catabolic rates of rapidly growing tumors. This enzyme converts the incoming glucose to glucose-6-phosphate, the initial phosphorylated intermediate of the glycolytic pathway and an important precursor of many cellular "building blocks." At the genetic level the tumor cell adapts metabolically by first increasing the gene copy number of Type II hexokinase. The enzyme's gene promoter, in turn, shows a wide promiscuity toward the signal transduction cascades active within tumor cells. It is activated by glucose, insulin, low oxygen "hypoxic" conditions, and phorbol esters, all of which enhance the rate of transcription. Also, the tumor cell uses the tumor suppressor p53, which is usually modified by mutations to debilitate cell cycle controls, to further activate hexokinase gene transcription. This results in both enhanced levels of the enzyme, which binds to mitochondrial porins thus gaining preferential access to mitochondrially generated ATP, and in a decreased susceptibility to product inhibition and proteolytic degradation. Significantly, these multiple strategies all work together to enable tumor cells to develop a metabolic strategy compatible with rapid proliferation and prolonged survival.

Animals↗

PubMed2005

Characterization of a plant, tyrosine-specific phosphatase of the aspartyl class.

The Arabidopsis thaliana homologue of the Eyes Absent genes (AtEYA) encodes a protein corresponding to the C-terminal conserved domain of the animal Eyes Absent proteins. We show here that AtEYA is a tyrosine-specific phosphatase that hydrolyzes its substrates in a metal-dependent reaction analogous to the phosphoserine phosphatases of the haloacid dehalogenase (HAD) family. The animal Eyes Absent proteins are a novel family of dual-function enzymes: they are transcription factors as well as phosphatases. They also represent a new mechanistic class of tyrosine phosphatases (PTPs) that do not have the Cys-containing signature motif. In contrast, AtEYA is only a tyrosine phosphatase and has no transactivation domain. Using the reaction mechanism of other HAD family enzymes as a model, we have conducted mutational analyses on AtEYA to query the roles of conserved residues. This analysis confirms the importance of the putative nucleophile, the general acid, and the metal-binding residues. Additionally, an inhibitory profile that is diagnostic of this new class of protein tyrosine phosphatases is described. The results of these studies on AtEYA reveal that while the animal and plant Eyes Absent proteins catalyze the same dephosphorylation reaction, the details of their specificity and active site environment, as well as their biological roles, are distinct.

Animals↗

PubMed2005

ATP induces conformational changes of periplasmic loop regions of the maltose ATP-binding cassette transporter.

We have studied cofactor-induced conformational changes of the maltose ATP-binding cassette transporter by employing limited proteolysis in detergent solution. The transport complex consists of one copy each of the transmembrane subunits, MalF and MalG, and of two copies of the nucleotide-binding subunit, MalK. Transport activity further requires the periplasmic maltose-binding protein, MalE. Binding of ATP to the MalK subunits increased the susceptibility of two tryptic cleavage sites in the periplasmic loops P2 of MalF and P1 of MalG, respectively. Lys(262) of MalF and Arg(73) of MalG were identified as probable cleavage sites, resulting in two N-terminal peptide fragments of 29 and 8 kDa, respectively. Trapping the complex in the transition state by vanadate further stabilized the fragments. In contrast, the tryptic cleavage profile of MalK remained largely unchanged. ATP-induced conformational changes of MalF-P2 and MalG-P1 were supported by fluorescence spectroscopy of complex variants labeled with 2-(4'-maleimidoanilino)naphthalene-6-sulfonic acid. Limited proteolysis was subsequently used as a tool to study the consequences of mutations on the transport cycle. The results suggest that complex variants exhibiting a binding protein-independent phenotype (MalF500) or containing a mutation that affects the "catalytic carboxylate" (MalKE159Q) reside in a transition state-like conformation. A similar conclusion was drawn for a complex containing a replacement of MalKQ140 in the signature sequence by leucine, whereas substitution of lysine for Gln(140) appears to lock the transport complex in the ground state. Together, our data provide the first evidence for conformational changes of the transmembrane subunits of an ATP-binding cassette import system upon binding of ATP.

ATP-Binding Cassette Transporters↗

PubMed2026

LymphGen-Sig: Integrating Genetic and Transcriptional States to Predict Therapeutic Response in Diffuse Large B-Cell Lymphoma.

PURPOSE: Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity and incomplete classification and do not incorporate nongenetic features that affect disease biology and therapeutic outcomes. To address these limitations, we developed LG-sig (LGsig), a gene expression-based platform that classifies all DLBCLs and harmonizes both genetic and nongenetic dimensions of the disease. METHODS: LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (National Cancer Institute/British Columbia Cancer Agency; N = 764). Model development was restricted to DLBCLs classified into MYD88L265P and CD79B mutations (MCD), BCL6 translocation and NOTCH2 mutations (BN2), EZH2 mutations and BCL2 translocation (EZB), or SGK1 and TET2 mutations (ST2). Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated as MCDsig, BN2sig, ST2sig, and EZBsig. The final model was applied to RNAseq from archival samples from the POLARIX trial (N = 678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for each LGsig subtype. RESULTS: LGsig accurately identified LG subtypes using transcriptional data alone and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. In addition, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and TP53 alterations, into more biologically and therapeutically relevant LGsig clusters. Finally, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases. CONCLUSION: LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.

Journal Article↗

PubMed2005

Gametophytic selection in Arabidopsis thaliana supports the selective model of intron length reduction.

Why do highly expressed genes have small introns? This is an important issue, not least because it provides a testing ground to compare selectionist and neutralist models of genome evolution. Some argue that small introns are selectively favoured to reduce the costs of transcription. Alternatively, large introns might permit complex regulation, not needed for highly expressed genes. This "genome design" hypothesis evokes a regionalized model of control of expression and hence can explain why intron size covaries with intergene distance, a feature also consistent with the hypothesis that highly expressed genes cluster in genomic regions with high deletion rates. As some genes are expressed in the haploid stage and hence subject to especially strong purifying selection, the evolution of genes in Arabidopsis provides a novel testing ground to discriminate between these possibilities. Importantly, controlling for expression level, genes that are expressed in pollen have shorter introns than genes that are expressed in the sporophyte. That genes flanking pollen-expressed genes have average-sized introns and intergene distances argues against regional mutational biases and genomic design. These observations thus support the view that selection for efficiency contributes to the reduction in intron length and provide the first report of a molecular signature of strong gametophytic selection.

Arabidopsis↗

PubMed2003

Substitutional mutations in the uncoupling protein-specific sequences of mitochondrial uncoupling protein UCP1 lead to the reduction of fatty acid-induced H+ uniport.

Mutants were constructed for mitochondrial uncoupling protein UCP1, with single or multiple substitutions within or nearby the UCP-signatures located in the first alpha-helix and second matrix-segment, using the QuickChange site directed mutagenesis protocol (Stratagene), and were assayed fluorometrically for kinetics of fatty acid (FA)-induced H+ uniport and for Cl- uniport. Their ability to bind 3H-GTP was also evaluated. The wild type UCP1 was associated with the FA-induced H+ uniport proportional to the added protein with a Km for lauric acid of 43 micro M and Vmax of 18 micro molmin(-1)(mg protein)(-1). Neutralization of Arg152 (in the second matrix-segment UCP-signature) led to approximately 50% reduction of FA affinity (reciprocal Km) and of Vmax for FA-induced H+ uniport. Halved FA affinity and 70% reduction of Vmax was found for the double His substitution outside the signature (H145L and H147L mutant). Neutralization of Asp27 in the first alpha-helix UCP-signature (D27V mutant) resulted in 75% reduction of FA affinity and approximately 50% reduction of Vmax, whereas the triple C24A and D27V and T30A mutant was fully non-functional (Vmax reduced by 90%). Interestingly, the T30A mutant exhibited only the approximately 50% reduced FA affinity but not Vmax. Cl- uniport and 3H-GTP binding were preserved in all studied mutants. We conclude that amino acid residues of the first alpha-helix UCP signature may be required to hold the intact UCP1 transport conformation. This could be valid also for the positive charge of Arg152 (second matrix-segment UCP signature), which may alternatively mediate FA interaction with the native protein.

Amino Acid Substitution↗

PubMed2004

Rat alpha- and beta-parvalbumins: comparison of their pentacarboxylate and site-interconversion variants.

Introduction of a fifth carboxylate into the ligand array of the CD site (via the combined S55D and E59D mutations) or the EF site (G98D) of rat alpha-parvalbumin substantially increases divalent ion affinity. This behavior, in conflict with that seen in model peptide systems, agrees with existing data for rat beta-parvalbumin [Henzl et al. (1996) Biochemistry 35, 5856-5869]. The complete analysis of the S55D/E59D double variant necessitated characterization of alpha E59D. Whereas the D59E mutation has minimal influence on beta CD site affinity, E59D has a major impact on the alpha CD site, lowering the apparent association constant by a factor of 14. The thermodynamic consequences of exchanging the rat alpha CD and EF site ligand arrays, which differ at the +z and -x coordination positions, were also examined. When the alpha CD array is imported into the EF site, it acquires a low-affinity phenotype, in agreement with previous findings for beta [Henzl et al. (1998) Biochemistry 37, 9101-9111]. However, when the EF ligand array is introduced into the alpha CD binding loop, it retains a high-affinity signature. This result, contrary to that observed in beta, suggests that the influence of the parvalbumin CD site environment supersedes the intrinsic behavior of the ligand array, a conclusion further supported by the disparate impact of the beta D59E and alpha E59D mutations.

Amino Acid Sequence↗

PubMed2001

Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations of the VHL gene. Recent studies suggest that VHL protein (pVHL) is a component of an E3 ubiquitin ligase, but the detailed biological function of pVHL remains to be determined. To further elucidate the biological functions of pVHL, we searched pVHL-interacting proteins using yeast two-hybrid screening. A novel protein named VHL-interacting deubiquitinating enzyme 1 (VDU1) was identified as being able to directly interact with pVHL in vitro and in vivo. We have determined the full-length cDNA of this enzyme, which includes two putative subtypes. Type I consists of 942 amino acids, and type II consists of 911 amino acids with predicted molecular masses of 107 and 103 kDa, respectively. We have also cloned a mouse homologue of this enzyme. Sequence analysis reveals that this protein is conserved between human and mouse and contains the signature motifs of the ubiquitin-specific processing protease family. Enzymatic function studies demonstrate its deubiquitinating activity. We have determined that the VDU1-interacting region in pVHL is located in its beta-domain, and several naturally occurring mutations located in this domain disrupt the interaction between pVHL and VDU1 protein. Co-immunoprecipitation demonstrates that VDU1 can be recruited into the pVHL-elongin C-elongin B complex. Finally, we demonstrate that VDU1 is able to be ubiquitinated via a pVHL-dependent pathway for proteasomal degradation, and VHL mutations that disrupt the interaction between VDU1 and pVHL abrogate the ubiquitination of VDU1. Our findings indicate that VDU1, a novel ubiquitin-specific processing protease, is a downstream target for ubiquitination and degradation by pVHL E3 ligase. Targeted degradation of VDU1 by pVHL could be crucial for regulating the ubiquitin-proteasome degradation pathway.

Amino Acid Sequence↗

PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗

PubMed1997

Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.

BACKGROUND: Mutations that map to the KvLQT1 gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the KvLQT1 and minK proteins functionally interact to generate a current with biophysical properties similar to I(Ks), the slowly activating delayed-rectifier cardiac potassium current. Since I(Ks) modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in KvLQT1 reduce I(Ks), resulting in the prolongation of cardiac action potential duration. METHODS AND RESULTS: We expressed LQTS-associated KvLQT1 mutants in Xenopus oocytes either individually or in combination with wild-type KvLQT1 or in combination with both wild-type KvLQT1 and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion. CONCLUSIONS: In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I(Ks) current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

Animals↗

PubMed2001

Physical interaction of CcmC with heme and the heme chaperone CcmE during cytochrome c maturation.

Biogenesis of c-type cytochromes requires the covalent attachment of heme to the apoprotein. In Escherichia coli, this process involves eight membrane proteins encoded by the ccmABCDEFGH operon. CcmE binds heme covalently and transfers it to apocytochromes c in the presence of other Ccm proteins. CcmC is necessary and sufficient to incorporate heme into CcmE. Here, we report that the CcmC protein directly interacts with heme. We further show that CcmC co-immunoprecipitates with CcmE. CcmC contains two conserved histidines and a signature sequence, the so-called tryptophan-rich motif, which is the only element common to cytochrome c maturation proteins of bacteria, archae, plant mitochondria, and chloroplasts. We report that mutational changes of these motifs affecting the function of CcmC in cytochrome c maturation do not influence heme binding of CcmC. However, the mutants are defective in the CcmC-CcmE interaction, suggesting that these motifs are involved in the formation of a CcmC-CcmE complex. We propose that CcmC, CcmE, and heme interact directly with each other, establishing a periplasmic heme delivery pathway for cytochrome c maturation.

Amino Acid Sequence↗

PubMed2002

Separable gating mechanisms in a Mammalian pacemaker channel.

Despite permeability to both K(+) and Na(+), hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels contain the K(+) channel signature sequence, GYG, within the selectivity filter of the pore. Here, we show that this region is involved in regulating gating in a mouse isoform of the pacemaker channel (mHCN2). A mutation in the GYG sequence of the selectivity filter (G404S) had different effects on the two components of the wild-type current; it eliminated the slowly activating current (I(f)) but, surprisingly, did not affect the instantaneous current (I(inst)). Confocal imaging and immunocytochemistry showed G404S protein on the periphery of the cells, consistent with the presence of channels on the plasma membrane. Experiments with the wild-type channel showed that the rate of I(f) deactivation and I(f) amplitude had a parallel dependence on the ratio of K(+)/Na(+) driving forces. In addition, the amplitude of fully activated I(f), unlike I(inst), was not well predicted by equal and independent flow of K(+) and Na(+). The data are consistent with two separable gating mechanisms associated with pacemaker channels: one (I(f)) that is sensitive to voltage, to a mutation in the selectivity filter, and to driving forces for permeating cations and another (I(inst)) that is insensitive to these influences.

Amino Acid Sequence↗

PubMed2005

Genetic variation in West Nile virus from naturally infected mosquitoes and birds suggests quasispecies structure and strong purifying selection.

Intrahost genetic diversity was analysed in naturally infected mosquitoes and birds to determine whether West Nile virus (WNV) exists in nature as a quasispecies and to quantify selective pressures within and between hosts. WNV was sampled from ten infected birds and ten infected mosquito pools collected on Long Island, NY, USA, during the peak of the 2003 WNV transmission season. A 1938 nt fragment comprising the 3' 1159 nt of the WNV envelope (E) coding region and the 5' 779 nt of the non-structural protein 1 (NS1) coding region was amplified and cloned and 20 clones per specimen were sequenced. Results from this analysis demonstrate that WNV infections are derived from a genetically diverse population of genomes in nature. The mean nucleotide diversity was 0.016 % within individual specimens and the mean percentage of clones that differed from the consensus sequence was 19.5 %. WNV sequences in mosquitoes were significantly more genetically diverse than WNV in birds. No host-dependent bias for particular types of mutations was observed and estimates of genetic diversity did not differ significantly between E and NS1 coding sequences. Non-consensus clones obtained from two avian specimens had highly similar genetic signatures, providing preliminary evidence that WNV genetic diversity may be maintained throughout the enzootic transmission cycle, rather than arising independently during each infection. Evidence of purifying selection was obtained from both intra- and interhost WNV populations. Combined, these data support the observation that WNV populations may be structured as a quasispecies and document strong purifying natural selection in WNV populations.

Animals↗

PubMed1998

Genetic variation in a human immunodeficiency virus type 2 live-virus Macaca nemestrina vaccine model.

Four pigtailed macaques were inoculated with an infectious, apathogenic human immunodeficiency virus type 2 (HIV-2) molecular clone (HIV-2KR) and subsequently challenged with a highly pathogenic strain, HIV-2287, together with two naive control animals. After challenge, two animals inoculated with a high dose of the immunizing strain were protected from CD4 decline and immunodeficiency. To examine the role of genetic heterogeneity in protection, fragments of the env gene were amplified from peripheral blood mononuclear cell DNA and plasma RNA of challenged animals by PCR, examined by using a heteroduplex tracking assay (HTA), and sequenced. By HTA, variation was detected principally within the V1 and V2 regions of envelope. Extent of variation in viral DNA clones as assessed by HTA correlated with inoculum size, as did the degree of variation in sequences of clones derived from viral DNA. Conversely, a rapid reduction in the number of plasma viral RNA variants was noted by HTA at 8 weeks postinfection in protected animals; this reduction was not present in naive or unprotected macaques. Sequences derived from plasma viral RNA were found to be more closely related than corresponding viral DNA sequences, and protection correlated with a significant reduction in variation in plasma RNA sequences in animals given the identical inocula of HIV-2287. Nonsynonymous mutations were significantly less prevalent in the protected animals. An additional potential glycosylation site was predicted to be present in the V2 region in all but one clone, and amino acid signatures related to protection were identified in viral DNA and RNA clones within both the V1 and V2 regions. Examination of the role of viral variation in this HIV-2 live-virus vaccine model may provide valuable insights into immunopathogenesis.

Amino Acid Sequence↗

PubMed2026

Integrated Immunotherapy Target Atlas for Ewing Sarcoma.

BACKGROUND/AIM: Ewing sarcoma is a fusion-driven malignancy with low tumor mutational burden, making recurrent tumor-associated antigens with favorable tumor-to-normal contrast central to immunotherapy development. We converted the Deng et al.-defined 32-gene Ewing Sarcoma Specific Signature (ESS32) into a practical target atlas by integrating tumor RNA expression with normal-tissue context, protein evidence, subcellular localization, and therapeutic accessibility. MATERIALS AND METHODS: A 38-gene set was analyzed, including ESS32 and six comparator antigens (STEAP1, LINGO1, PRAME, CD99, CD276/B7-H3, and ENPP1). Eight Gene Expression Omnibus datasets (n=854 samples) were assigned predefined roles spanning tumor-versus-skeletal-muscle comparison, broad normal-organ context, EWSR1::FLI1 perturbation, tumor-only support cohorts, cell-line models, and cross-sarcoma comparison. Results were overlaid with Human Protein Atlas and published proteomic/surfaceome evidence. RESULTS: In GSE17674, the strongest tumor-enriched transcripts included NKX2-2, NPY1R, STEAP1, RBM11, RNF182, LIPI, CD99, STEAP2, LOXHD1, and DCDC2. Normal-tissue and compartment data substantially reordered RNA-only ranking. NKX2-2 showed the strongest Ewing-associated signal but encodes a nuclear transcription factor, favoring peptide-HLA/T-cell receptor (TCR) or vaccine development. RBM11 and LIPI emerged as high-interest intracellular/secretome-associated candidates, with an explicit epididymal/male reproductive caveat for LIPI. CD99 and NPY1R illustrated normal-cell reservoir and receptor-distribution constraints. CONCLUSION: ESS32 should be interpreted as an EWSR1::FLI1-associated RNA discovery set, not as a pre-validated target panel. Practical nomination requires integration of RNA enrichment, normal-tissue distribution, protein evidence, cellular compartment, and modality compatibility before nomination of TCR, vaccine, antibody-drug conjugate (ADC), chimeric antigen receptor (CAR), radioligand, or validation-first candidates.

Humans↗

PubMed2002

Bacillus subtilis inorganic pyrophosphatase: the C-terminal signature sequence is essential for enzyme activity and conformational integrity.

Bacillus subtilis inorganic pyrophosphatase is the first member of a newly identified Family II of PPases. To examine the role of a signature sequence found near the C-terminus, two truncated variants and a series of site-specific mutants were produced. A truncation of 17 residues (17AATR) but also single alanine substitutions, R295A and K296A, produced inactive enzyme. Removal of 5 nonconserved terminal residues (5AATR) markedly affected enzyme stability. Replacing S294 with A, T, C, or V decreased activity, the latter two mutations showing the greatest effect. Substitutions V299I and V300I had no or minor effects, whereas V300W and V299G/V300W significantly reduced activity. The sizes of truncated proteins and the full-length PPase were indistinguishable by gel-filtration. We conclude that the C-terminus has no role in multimerization, while both its conserved and nonconserved regions are essential for full enzyme activity. The signature sequence is required for both the conformation and composition of the active site.

Bacillus subtilis↗