Publications by authors named "Yuelin J Zhu"

26 Publications

  • Page 1 of 1

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
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http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642810PMC
November 2021

Mutant Cooperates with a Fusion to Induce Early Immature Thymocyte Precursor ALL.

Cancer Res 2021 Oct 28;81(19):5033-5046. Epub 2021 Jul 28.

Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Mutations in the isocitrate dehydrogenase 1 () and genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated transgenic mice to examine the role of the mutation in leukemia. No leukemia developed in transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from fusion () transgenic mice frequently acquire somatic mutations when they transform to acute myeloid leukemia, we generated double transgenic mice. transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including , and were also found in DN1/DN2 T-ALL. treatment of thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that mice can serve as a useful model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy. SIGNIFICANCE: T-cell leukemia induced in mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487989PMC
October 2021

The S-phase-induced lncRNA promotes cell proliferation by controlling YAP1/Hippo signaling pathway.

Elife 2020 10 27;9. Epub 2020 Oct 27.

Department of Cell and Developmental Biology, Cancer center at Illinois, University of Illinois at Urbana-Champaign, Urbana, United States.

Cell cycle is a cellular process that is subject to stringent control. In contrast to the wealth of knowledge of proteins controlling the cell cycle, very little is known about the molecular role of lncRNAs (long noncoding RNAs) in cell-cycle progression. By performing genome-wide transcriptome analyses in cell-cycle-synchronized cells, we observed cell-cycle phase-specific induction of >2000 lncRNAs. Further, we demonstrate that an S-phase-upregulated lncRNA, , facilitates cell-cycle progression by promoting YAP1-mediated gene expression. facilitates the cell-cycle-specific transcription of , a positive regulator of YAP1, by promoting the co-activator, DDX5-mediated stabilization of RNA polymerase II on chromatin. Finally, elevated levels are associated with poor cancer prognosis and tumorigenicity, implying its pro-survival role. Thus, we demonstrate the role of a S-phase up-regulated lncRNA in cell-cycle progression modulating the expression of genes controlling cell proliferation.
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http://dx.doi.org/10.7554/eLife.55102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591261PMC
October 2020

1q21.1 deletion and a rare functional polymorphism in siblings with thrombocytopenia-absent radius-like phenotypes.

Cold Spring Harb Mol Case Stud 2019 12 13;5(6). Epub 2019 Dec 13.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20859, USA.

Thrombocytopenia-absent radii (TAR) syndrome, characterized by neonatal thrombocytopenia and bilateral radial aplasia with thumbs present, is typically caused by the inheritance of a 1q21.1 deletion and a single-nucelotide polymorphism in on the nondeleted allele. We evaluated two siblings with TAR-like dysmorphology but lacking thrombocytopenia in infancy. Family NCI-107 participated in an IRB-approved cohort study and underwent comprehensive clinical and genomic evaluations, including aCGH, whole-exome, whole-genome, and targeted sequencing. Gene expression assays and electromobility shift assays (EMSAs) were performed to evaluate the variant of interest. The previously identified TAR-associated 1q21.1 deletion was present in the affected siblings and one healthy parent. Multiple sequencing approaches did not identify previously described TAR-associated SNPs or mutations in relevant genes. We discovered rs61746197 A > G heterozygosity in the parent without the deletion and apparent hemizygosity in both siblings. rs61746197 A > G overlaps a RelA-p65 binding motif, and EMSAs indicate the A allele has higher transcription factor binding efficiency than the G allele. Stimulation of K562 cells to induce megakaryocyte differentiation abrogated the shift of both reference and alternative probes. The 1q21.1 TAR-associated deletion in combination with the G variant of rs61746197 on the nondeleted allele is associated with a TAR-like phenotype. rs61746197 G could be a functional enhancer/repressor element, but more studies are required to identify the specific factor(s) responsible. Overall, our findings suggest a role of rs61746197 A > G and human disease in the setting of a 1q21.1 deletion on the other chromosome.
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http://dx.doi.org/10.1101/mcs.a004564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913155PMC
December 2019

Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.

Sci Rep 2019 11 20;9(1):17213. Epub 2019 Nov 20.

Genetics Branch, Center for cancer Research, NCI/NIH, Bethesda, MD, USA.

Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8- double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1 + Kit + (LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.
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http://dx.doi.org/10.1038/s41598-019-53610-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868234PMC
November 2019

A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.

Mice homozygous for a hypomorphic allele of DNA replication factor minichromosome maintenance protein 2 (designated Mcm2cre/cre) develop precursor T cell lymphoblastic leukemia/lymphoma (pre-T LBL) with 4-32 small interstitial deletions per tumor. Mice that express a NUP98-HOXD13 (NHD13) transgene develop multiple types of leukemia, including myeloid and T and B lymphocyte. All Mcm2cre/cre NHD13+ mice develop pre-T LBL, and 26% develop an unrelated, concurrent B cell precursor acute lymphoblastic leukemia (BCP-ALL). Copy number alteration (CNA) analysis demonstrated that pre-T LBLs were characterized by homozygous deletions of Pten and Tcf3 and partial deletions of Notch1 leading to Notch1 activation. In contrast, BCP-ALLs were characterized by recurrent deletions involving Pax5 and Ptpn1 and copy number gain of Abl1 and Nup214 resulting in a Nup214-Abl1 fusion. We present a model in which Mcm2 deficiency leads to replicative stress, DNA double strand breaks (DSBs), and resultant CNAs due to errors in DNA DSB repair. CNAs that involve critical oncogenic pathways are then selected in vivo as malignant lymphoblasts because of a fitness advantage. Some CNAs, such as those involving Abl1 and Notch1, represent attractive targets for therapy.
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http://dx.doi.org/10.1172/jci.insight.131434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962024PMC
December 2019

Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background.

Blood 2019 06 16;133(24):2610-2614. Epub 2019 Apr 16.

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.

Approximately 10% of mice develop an aggressive acute lymphoblastic leukemia of B-1 lymphocyte progenitor origin (pro-B1 ALL), accompanied by somatic frameshift mutations of the BCL6 interacting corepressor () gene, most commonly within a 9-bp "hotspot" in exon 8. To determine whether experimentally engineered mutations would lead to pro-B1 ALL, we used clustered, regularly interspaced, short palindromic repeats-associated protein 9 to introduce a frameshift mutation into hematopoietic stem and progenitor cells through the use of small guide RNAs ( sgRNAs). Recipient mice transplanted with bone marrow or fetal liver cells that had been transduced with a sgRNA developed pro-B1 ALL, characterized by a B-1 progenitor immunophenotype, clonal Igh gene rearrangement, and indel mutation, whereas control recipients did not. Similar to a subset of human B-cell precursor ALL, the murine pro-B1 ALL had acquired somatic mutations in Jak kinase genes. JAK inhibitors (ruxolitinib and tofacitinib) inhibited the growth of pro-B1 ALL cell lines established from Bcor sgRNA/NP23 recipients at clinically achievable concentrations (100 nM). Our results demonstrate that mutations collaborate with to induce pro-B1 ALL, and that JAK inhibitors are potential therapies for pro-B1 ALL.
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http://dx.doi.org/10.1182/blood.2018864173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566592PMC
June 2019

Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells.

Sci Rep 2019 03 14;9(1):4544. Epub 2019 Mar 14.

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Many tumors maintain chromosome-ends through a telomerase-independent, DNA-templated mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes ATRX and DAXX, which encode components of an H3.3 histone chaperone complex. The role of ATRX and DAXX mutations in potentiating the mechanism of ALT remains incompletely understood. Here we characterize an osteosarcoma cell line, G292, with wild-type ATRX but a unique chromosome translocation resulting in loss of DAXX function. While ATRX and DAXX form a complex in G292, this complex fails to localize to nuclear PML bodies. We demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores the localization of ATRX/DAXX to PML bodies. Using an inducible system, we show that ALT-associated PML bodies are disrupted rapidly following DAXX induction and that ALT is again restored following withdrawal of DAXX.
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http://dx.doi.org/10.1038/s41598-019-41058-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418139PMC
March 2019

Dynamics of Genome Alterations in Crohn's Disease-Associated Colorectal Carcinogenesis.

Clin Cancer Res 2018 10 2;24(20):4997-5011. Epub 2018 Jul 2.

Institute of Pathology, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Patients with inflammatory bowel diseases, that is, ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in patients with CD are poorly characterized. Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next-generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization. The results were compared with 24 sporadic CRCs with similar histomorphology (i.e., mucinous adenocarcinomas), and to The Cancer Genome Atlas data (TCGA). CD-CRCs showed somatic copy-number alterations (SCNAs) similar to sporadic CRCs with one notable exception: the gain of 5p was significantly more prevalent in CD-CRCs. CD-CRCs had a distinct mutation signature: (76% in CD-CRCs vs. 33% in sporadic mucinous CRCs), (24% vs. 50%), (17% vs. 75%), and (3% vs. 29%). mutations and SCNAs were early and frequent events in CD progression, while , and mutations occurred later. In four patients with CD-CRC, at least one mutation and/or SCNAs were already present in non-dysplastic colonic mucosa, indicating occult tumor evolution. Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predicting disease progression and distinguishes CD-associated from sporadic colorectal neoplasia. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080970PMC
October 2018

Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways.

Blood Adv 2017 Sep 8;1(20):1749-1759. Epub 2017 Sep 8.

Genetics Branch and.

B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in - () transgenic mice. The immunophenotype (Lin B220 CD19 AA4.1) was identical to that of progenitor (pro) B-1 cells, and V gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells. Moreover, the gene expression profile of these leukemias was most similar to that of fetal liver pro-B fraction BC, a known source of B-1 B cells, further supporting a pro-B-1 origin of these leukemias. The pro-B-1 acute lymphoblastic leukemias (ALLs) acquired spontaneous mutations in both and Janus kinase () pathway (// and ) genes, supporting a hypothesis that mutations in 3 critical pathways (stem-cell self-renewal, B-cell differentiation, and cytokine signaling) collaborate to induce B-cell precursor (BCP) ALL. Finally, the thymic stromal lymphopoietin (Tslp) cytokine is required for murine B-1 development, and chromosomal rearrangements resulting in overexpression of the TSLP receptor (CRLF2) are present in some patients with high-risk BCP-ALL (referred to as r ALL). Gene expression profiles of pro-B-1 ALL were more similar to that of r ALL than non-r ALL, and analysis of V gene usage from patients with ALL demonstrated preferential usage of V regions used by human B-1 B cells, leading to the suggestion that this subset of patients with BCP-ALL has a malignancy of B-1, rather than B-2, B-cell origin.
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http://dx.doi.org/10.1182/bloodadvances.2017009837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728343PMC
September 2017

Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.

Cancer Cell 2017 07 22;32(1):57-70.e3. Epub 2017 Jun 22.

Georgetown University Medical Center, Washington, DC 20057, USA.

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integration of genomics, transcriptomics, and metabolomics. While ICC and HCC share recurrently mutated genes, including TP53, ARID1A, and ARID2, mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2, whereas the C2 subtype is linked to obesity, T cell infiltration, and bile acid metabolism. These molecular subtypes are found in 582 Asian, but less so in 265 Caucasian patients. Thus, Asian ICC and HCC, while clinically treated as separate entities, share common molecular subtypes with similar actionable drivers to improve precision therapy.
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http://dx.doi.org/10.1016/j.ccell.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524207PMC
July 2017

PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes.

Carcinogenesis 2017 10;38(10):966-975

Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, IL 61801,USA, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.
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http://dx.doi.org/10.1093/carcin/bgx062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410955PMC
October 2017

Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer.

J Clin Endocrinol Metab 2017 07;102(7):2268-2280

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Context: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated.

Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models.

Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells.

Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling.

Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.
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http://dx.doi.org/10.1210/jc.2016-3771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505205PMC
July 2017

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance.

Genes Chromosomes Cancer 2017 Jun 31;56(6):472-483. Epub 2017 Mar 31.

Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Malignant transformation is a multistep process that is dictated by the acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. However, it remains unclear whether the genetic events that occur during transformation are similar in mice and humans. To address that, we chose several transgenic mouse models of hematopoietic malignancies and identified acquired mutations in these mice by means of targeted re-sequencing of known cancer-associated genes as well as whole exome sequencing. We found that mutations that are typically found in acute myeloid leukemia or T cell acute lymphoblastic leukemia patients are also common in mouse models of the respective disease. Moreover, we found that the most frequent mutations found in a mouse model of lymphoma occur in a set of epigenetic modifier genes, implicating this pathway in the generation of lymphoma. These results demonstrate that genetically engineered mouse models (GEMM) mimic the genetic evolution of human cancer and serve as excellent platforms for target discovery and validation.
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http://dx.doi.org/10.1002/gcc.22451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399546PMC
June 2017

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model.

Clin Cancer Res 2017 Jan 20;23(2):430-440. Epub 2016 Jul 20.

Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.

Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbKras mouse, a model of anaplastic thyroid cancer.

Experimental Design: We treated ThrbKras mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.

Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.

Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241246PMC
January 2017

miR-23a impairs bone differentiation in osteosarcoma via down-regulation of GJA1.

Front Genet 2015 2;6:233. Epub 2015 Jul 2.

Genetics Branch, Center for Cancer Research, National Institutes of Health Bethesda, MD, USA.

Osteosarcoma is the most common type of bone cancer in children and adolescents. Impaired differentiation of osteoblast cells is a distinguishing feature of this aggressive disease. As improvements in survival outcomes have largely plateaued, better understanding of the bone differentiation program may provide new treatment approaches. The miRNA cluster miR-23a~27a~24-2, particularly miR-23a, has been shown to interact with genes important for bone development. However, global changes in gene expression associated with functional gain of this cluster have not been fully explored. To better understand the relationship between miR-23a expression and bone cell differentiation, we carried out a large-scale gene expression analysis in HOS cells. Experimental results demonstrate that over-expression of miR-23a delays differentiation in this system. Downstream bioinformatic analysis identified miR-23a target gene connexin-43 (Cx43/GJA1), a mediator of intercellular signaling critical to osteoblast development, as acutely affected by miR-23a levels. Connexin-43 is up-regulated in the course of HOS cell differentiation and is down-regulated in cells transfected with miR-23a. Analysis of gene expression data, housed at Gene Expression Omnibus, reveals that Cx43 is consistently up-regulated during osteoblast differentiation. Suppression of Cx43 mRNA by miR-23a was confirmed in vitro using a luciferase reporter assay. This work demonstrates novel interactions between microRNA expression, intercellular signaling and bone differentiation in osteosarcoma.
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http://dx.doi.org/10.3389/fgene.2015.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488756PMC
July 2015

Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

Nat Commun 2015 Apr 28;6:7048. Epub 2015 Apr 28.

Laboratory of Molecular Biology, CCR, NCI, NIH, Building 37/NIH, Bethesda, Maryland 20892, USA.

A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.
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http://dx.doi.org/10.1038/ncomms8048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309829PMC
April 2015

Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer.

Am J Cancer Res 2014 19;4(6):776-88. Epub 2014 Nov 19.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.

Undifferentiated thyroid carcinoma is one of the most aggressive human cancers. Although genetic changes underlying this aggressive cancer remain to be elucidated, RAS mutations have been frequently identified in it. Mice harboring a mutant thyroid hormone receptor Thrb(PV) (Thrb(PV/PV) ) spontaneously develop differentiated follicular thyroid carcinoma similar to human thyroid cancer. We recently demonstrated that targeting a RAS mutation (Kras(G12D) ) to the thyroid of Thrb(PV/PV) mice (Thrb(PV/PV) Kras(G12D) mice) promotes initiation and progression of undifferentiated thyroid cancer. To uncover genes destined to drive the aggressive cancer phenotype, we used cDNA microarrays to compare the gene expression profiles of thyroid cells of Kras(G12D) mice and thyroid tumor lesions of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Analyses of microarray data identified 14 upstream regulators that were significantly altered in thyroid tumors of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Most of these genes with altered expression function as key regulators in growth factor-induced signaling. Further analysis identified gene expression profiles of markedly elevated integrin levels, acting as upstream activators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of Thrb(PV/PV) Kras(G12D) mice. The present studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRβPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266711PMC
December 2014

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.

Nat Genet 2014 Aug 29;46(8):844-9. Epub 2014 Jun 29.

1] Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA. [2] Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA.

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.
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http://dx.doi.org/10.1038/ng.3016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705185PMC
August 2014

A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-κB signaling in chordoma biology.

PLoS One 2013 6;8(11):e79950. Epub 2013 Nov 6.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.

Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819300PMC
June 2014

Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer.

Genome Res 2013 Nov 12;23(11):1797-809. Epub 2013 Aug 12.

Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA;

Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation, and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function, but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome-wide DNA-binding and transcription data in EWSR1/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically coregulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F-ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWSR1/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target genes has a generally activating effect, EWSR1/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWSR1/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation.
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http://dx.doi.org/10.1101/gr.151340.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814880PMC
November 2013

The exomes of the NCI-60 panel: a genomic resource for cancer biology and systems pharmacology.

Cancer Res 2013 Jul 15;73(14):4372-82. Epub 2013 Jul 15.

Genetics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, and Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20982, USA.

The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893961PMC
July 2013

Polycomb repressor complex-2 is a novel target for mesothelioma therapy.

Clin Cancer Res 2012 Jan 25;18(1):77-90. Epub 2011 Oct 25.

Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).

Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.

Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.

Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310139PMC
January 2012

Genomic profiling of genes contributing to metastasis in a mouse model of thyroid follicular carcinoma.

Am J Cancer Res 2011 Jan;1(1):1-13

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Metastasis is the major cause of thyroid cancer-related death. However, little is known about the genes involved in the metastatic spread of thyroid carcinomas. We have created a mouse that spontaneously develops metastatic follicular thyroid carcinoma (FTC). This mouse harbors a targeted mutation (denoted TRβPV) in the thyroid hormone receptor β gene (Thrb(PV/PV) mice). Our recent studies show that the highly elevated level of thyroid stimulating hormone (TSH) in Thrb(PV/PV) mice promotes proliferation of thyroid tumor cells, but requires the collaboration of the oncogenic action of TRβPV to empower the tumor cells to undergo distant metastasis. To uncover genes destined to drive the metastatic process, we used cDNA microarrays to compare the genomic expression profile of laser capture microdissected thyroid tumor lesions of Thrb(PV/PV) mice with that of hyperplastic thyroid cells of wild-type mice having elevated TSH induced by treatment with the anti-thyroid drug propylthiouracil (WT-PTU mice). Analyses of microarray data indicated that the expressions of 150 genes were significantly altered between Thrb(PV/PV) and WT-PTU mice (87 genes had higher expression and 63 genes had lower expression in Thrb(PV/PV) mice than in WT-PTU mice). Thirty-six percent of genes with altered expression function as key regulators in metastasis. The remaining genes were involved in various cellular processes including metabolism, intracellular trafficking, transcriptional regulation, post-transcriptional modification, and cell-cell/extracellular matrix signaling. The present studies have uncovered novel genes responsible for the metastatic spread of FTC and, furthermore, have shown that the metastatic process of thyroid cancer requires effective collaboration among genes with diverse cellular functions. Importantly, the present studies indicate that the tumor cells in the primary lesions are endowed with the genes destined to promote metastasis. Thus, our study has provided new insights into the understanding of the metastatic spread of human thyroid cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090007PMC
January 2011

Global expression profiling reveals gain-of-function oncogenic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis.

Am J Cancer Res 2011 ;1(2):168-191

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (Thrb(PV/PV) mice) was used in the present study. The Thrb(PV/PV) mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in Thrb(PV/PV) mice and Thra1(-/-)Thrb(-/-) mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of Thrb(PV/PV) mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in Thrb(PV/PV) mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote thyroid carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086765PMC
January 2011
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