Ontology highlight
ABSTRACT:
PROVIDER: PRJEB26337 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Targeted next-generation sequencing was performed in patients with IDH1 or IDH2 mutations. Here we describe 4 cases where mutant IDH isoform switching serves as a mechanism of acquired clinical resistance to mutant IDH inhibition.
2018-10-24 | PRJEB29344 | EVA
Project description:Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia. R-2HG-mediated CD44 upregulation is found in IDH-mutant AML patients of different cohorts. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances killing of IDH-mutant leukemia cells and overcomes resistance to IDH inhibition. Hence, we uncover an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.
2025-01-24 | GSE238058 | GEO
Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition.
| PRJNA803137 | ENA
Project description:ATR is a PI3K-like kinase protein, regulating checkpoint responses to DNA damage and replication stress. Apart from its checkpoint function in the nucleus, ATR actively engage in antiapoptotic role at mitochondria following DNA damage. The different functions of ATR in the nucleus and cytoplasm are carried out by two prolyl isomeric forms of ATR: trans- and cis-ATR, respectively. The isomerization occurs at the Pin1 Ser428-Pro429 motif of ATR. Here we investigated the structural basis of the subcellular location-specific functions of human ATR. Using a mass spectrometry-based footprinting approach, the surface accessibility of ATR lysine residues to sulfo-NHS-LC-biotin modification was monitored and compared between the cis and the trans-isomers. We have identified two biotin-modified lysine residues, K459 and K469, within the BH3-like domain of cis-ATR that were not accessible in trans-ATR, indicating a conformational change around the BH3 domain between cis- and trans-ATR. The conformational alteration also involved the N-terminal domain and the middle HEAT domain. Moreover, experimental results from an array of complementary assays show that cis-ATR with the accessible BH3 domain was able to bind to tBid while trans-ATR could not. In addition, both cis- and trans-ATR can directly form homodimers via their C-terminal domains without ATRIP, while nuclear (trans-ATR) in the presence of ATRIP forms dimer-dimer complexes involving both N- and C-termini of ATR and ATRIP after UV. Structural characteristics around the Ser428-Pro429 motif and the BH3 domain region are also analyzed by molecular modelling and dynamics simulation. In support, cis conformation was found to be significantly more energetically favourable than trans at Ser428-Pro429 bond in a 20-aa wild-type ATR peptide. Taken together, our results suggest that the isomerization-induced structural changes of ATR define both its subcellular location and compartment-specific functions and plays an essential role in promoting cell survival and DNA damage responses.
2022-08-12 | PXD031385 | Pride
Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition [RNA-seq]
| PRJNA803146 | ENA
Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition [CHIP-seq]
| PRJNA803145 | ENA
Project description:Variation in gene expression arises from cis- and trans-regulatory mutations, which contribute differentially to expression divergence. Here, we compare the impacts on gene expression and fitness for cis- and trans-regulatory mutations affecting expression of the TDH3 gene in Saccharomyces cerevisiae. We use the effects of cis-regulatory mutations to isolate effects of trans-regulatory mutations caused by impacts on TDH3 from pleiotropic impacts on other genes, providing a rare distribution of pleiotropic effects. These pleiotropic effects were often, but not always, deleterious. For cis- and trans-regulatory mutations with similar effects on TDH3, trans-regulatory mutations had more widespread effects on gene expression, with distinct impacts on expression of genes downstream of TDH3. These differences between cis-and trans-regulatory mutations help explain their different contributions to regulatory evolution.
2021-05-25 | GSE175398 | GEO
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153348 | GEO
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153347 | GEO
Project description:Gene expression evolution can be caused by changes in cis- or trans-regulatory elements or both. As cis and trans regulation operate through different molecular mechanisms, cis and trans mutations may show different inheritance patterns and may be subjected to different selective constraints. To investigate these issues, we obtained and analyzed gene expression data from two Saccharomyces cerevisiae strains and their hybrid, using high-throughput sequencing. Our data indicate that compared to other types of genes, those with antagonistic cis-trans interactions are more likely to exhibit over- or under-dominant inheritance of expression level. Moreover, in accordance with previous studies, genes with trans variants tend to have a dominant inheritance pattern while cis variants are enriched for additive inheritance. In addition, cis regulatory differences contribute more to expression differences between species than within species, whereas trans regulatory differences show a stronger association between divergence and polymorphism. Our data indicate that in the trans component of gene expression differences genes subjected to weaker selective constraints tend to have an excess of polymorphism over divergence compared to those subjected to stronger selective constraints. In contrast, in the cis component, this difference between genes under stronger and weaker selective constraint is mostly absent. To explain these observations, we propose that purifying selection more strongly shapes trans polymorphism than cis polymorphism. Study the gene expression patterns in two strains of yeast (BY and RM)
2013-11-10 | E-GEOD-46838 | biostudies-arrayexpress