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1.
Blood ; 135(26): 2337-2353, 2020 06 25.
Article in English | MEDLINE | ID: mdl-32157296

ABSTRACT

Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.


Subject(s)
Blast Crisis/genetics , Gene Expression Regulation, Leukemic/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Polycomb Repressive Complex 1/physiology , Polycomb Repressive Complex 2/physiology , Cell Differentiation , Chromatin Immunoprecipitation , DNA Methylation , Datasets as Topic , Enhancer of Zeste Homolog 2 Protein/physiology , Gene Dosage , Gene Ontology , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 2/genetics , Transcriptome , Exome Sequencing , Whole Genome Sequencing
2.
Circulation ; 139(16): 1937-1956, 2019 04 16.
Article in English | MEDLINE | ID: mdl-30717603

ABSTRACT

BACKGROUND: The human genome folds in 3 dimensions to form thousands of chromatin loops inside the nucleus, encasing genes and cis-regulatory elements for accurate gene expression control. Physical tethers of loops are anchored by the DNA-binding protein CTCF and the cohesin ring complex. Because heart failure is characterized by hallmark gene expression changes, it was recently reported that substantial CTCF-related chromatin reorganization underpins the myocardial stress-gene response, paralleled by chromatin domain boundary changes observed in CTCF knockout. METHODS: We undertook an independent and orthogonal analysis of chromatin organization with mouse pressure-overload model of myocardial stress (transverse aortic constriction) and cardiomyocyte-specific knockout of Ctcf. We also downloaded published data sets of similar cardiac mouse models and subjected them to independent reanalysis. RESULTS: We found that the cardiomyocyte chromatin architecture remains broadly stable in transverse aortic constriction hearts, whereas Ctcf knockout resulted in ≈99% abolition of global chromatin loops. Disease gene expression changes correlated instead with differential histone H3K27-acetylation enrichment at their respective proximal and distal interacting genomic enhancers confined within these static chromatin structures. Moreover, coregulated genes were mapped out as interconnected gene sets on the basis of their multigene 3D interactions. CONCLUSIONS: This work reveals a more stable genome-wide chromatin framework than previously described. Myocardial stress-gene transcription responds instead through H3K27-acetylation enhancer enrichment dynamics and gene networks of coregulation. Robust and intact CTCF looping is required for the induction of a rapid and accurate stress response.


Subject(s)
Aortic Valve Stenosis/genetics , CCCTC-Binding Factor/metabolism , Chromatin/metabolism , Heart Failure/genetics , Myocytes, Cardiac/physiology , Acetylation , Animals , CCCTC-Binding Factor/genetics , Cells, Cultured , Chromatin Assembly and Disassembly , Disease Models, Animal , Epigenesis, Genetic , Gene Expression Regulation , Gene Ontology , Gene Regulatory Networks , Histones/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Stress, Physiological
3.
Clin Transl Med ; 14(6): e1723, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38877653

ABSTRACT

BACKGROUND: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. METHODS: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. RESULTS: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs. CONCLUSIONS: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.


Subject(s)
Cholangiocarcinoma , Pre-B-Cell Leukemia Transcription Factor 1 , Proto-Oncogene Proteins , Humans , Cholangiocarcinoma/genetics , Pre-B-Cell Leukemia Transcription Factor 1/genetics , Male , Proto-Oncogene Proteins/genetics , Female , Prognosis , Middle Aged , Aged , Bile Duct Neoplasms/genetics , Germany/epidemiology , Biomarkers, Tumor/genetics , Adult , Genomics/methods , Protein-Tyrosine Kinases
4.
Genome Biol ; 16: 32, 2015 Feb 12.
Article in English | MEDLINE | ID: mdl-25808843

ABSTRACT

BACKGROUND: Colorectal cancer with metastases limited to the liver (liver-limited mCRC) is a distinct clinical subset characterized by possible cure with surgery. We performed high-depth sequencing of over 750 cancer-associated genes and copy number profiling in matched primary, metastasis and normal tissues to characterize genomic progression in 18 patients with liver-limited mCRC. RESULTS: High depth Illumina sequencing and use of three different variant callers enable comprehensive and accurate identification of somatic variants down to 2.5% variant allele frequency. We identify a median of 11 somatic single nucleotide variants (SNVs) per tumor. Across patients, a median of 79.3% of somatic SNVs present in the primary are present in the metastasis and 81.7% of all alterations present in the metastasis are present in the primary. Private alterations are found at lower allele frequencies; a different mutational signature characterized shared and private variants, suggesting distinct mutational processes. Using B-allele frequencies of heterozygous germline SNPs and copy number profiling, we find that broad regions of allelic imbalance and focal copy number changes, respectively, are generally shared between the primary tumor and metastasis. CONCLUSIONS: Our analyses point to high genomic concordance of primary tumor and metastasis, with a thick common trunk and smaller genomic branches in general support of the linear progression model in most patients with liver-limited mCRC. More extensive studies are warranted to further characterize genomic progression in this important clinical population.


Subject(s)
Colorectal Neoplasms/genetics , Disease Progression , Genes, Neoplasm , High-Throughput Nucleotide Sequencing/methods , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Algorithms , Alleles , Allelic Imbalance/genetics , Base Sequence , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Computational Biology , Gene Frequency/genetics , Genome, Human , Humans , Liver Neoplasms/drug therapy , Molecular Sequence Data , Mutation/genetics , Neoplasms, Multiple Primary/genetics
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