Showing papers by "Todd R. Golub published in 2007"
TL;DR: It is shown that global repression of miRNA maturation promotes cellular transformation and tumorigenesis, and abrogation of global miRNA processing promotes tumorigenisation.
Abstract: MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers. However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.
1,400 citations
TL;DR: The data show that expression of many microRNAs is altered in heart disease and that different types of heart disease are associated with distinct changes in microRNA expression.
Abstract: MicroRNAs are recently discovered regulators of gene expression and are becoming increasingly recognized as important regulators of heart function. Genome-wide profiling of microRNAs in human heart...
646 citations
TL;DR: It is shown that expression signatures of as few as two miRNAs could accurately discriminate ALL from AML, and that epigenetic regulation might play an important role in the regulation of expression of miRNAAs in acute leukemias.
Abstract: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, whereas acute myeloid leukemia (AML) is the most common acute leukemia in adults. In general, ALL has a better prognosis than AML. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify markers for diagnosis and treatment, we performed a large-scale genome-wide microRNA (miRNA, miR) expression profiling assay and identified 27 miRNAs that are differentially expressed between ALL and AML. Among them, miR-128a and -128b are significantly overexpressed, whereas let-7b and miR-223 are significantly down-regulated in ALL compared with AML. They are the most discriminatory miRNAs between ALL and AML. Using the expression signatures of a minimum of two of these miRNAs resulted in an accuracy rate of >95% in the diagnosis of ALL and AML. The differential expression patterns of these four miRNAs were validated further through large-scale real-time PCR on 98 acute leukemia samples covering most of the common cytogenetic subtypes, along with 10 normal control samples. Furthermore, we found that overexpression of miR-128 in ALL was at least partly associated with promoter hypomethylation and not with an amplification of its genomic locus. Taken together, we showed that expression signatures of as few as two miRNAs could accurately discriminate ALL from AML, and that epigenetic regulation might play an important role in the regulation of expression of miRNAs in acute leukemias.
485 citations
TL;DR: An unsupervised subclass mapping method (SubMap), which reveals common subtypes between independent data sets and identifies common sub types of breast cancer associated with estrogen receptor status and a subgroup of lymphoma patients who share similar survival patterns, thus improving the accuracy of a clinical outcome predictor.
Abstract: Whole genome expression profiles are widely used to discover molecular subtypes of diseases. A remaining challenge is to identify the correspondence or commonality of subtypes found in multiple, independent data sets generated on various platforms. While model-based supervised learning is often used to make these connections, the models can be biased to the training data set and thus miss inherent, relevant substructure in the test data. Here we describe an unsupervised subclass mapping method (SubMap), which reveals common subtypes between independent data sets. The subtypes within a data set can be determined by unsupervised clustering or given by predetermined phenotypes before applying SubMap. We define a measure of correspondence for subtypes and evaluate its significance building on our previous work on gene set enrichment analysis. The strength of the SubMap method is that it does not impose the structure of one data set upon another, but rather uses a bi-directional approach to highlight the common substructures in both. We show how this method can reveal the correspondence between several cancer-related data sets. Notably, it identifies common subtypes of breast cancer associated with estrogen receptor status, and a subgroup of lymphoma patients who share similar survival patterns, thus improving the accuracy of a clinical outcome predictor.
389 citations
TL;DR: Findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.
242 citations
TL;DR: The concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations are supported.
196 citations
TL;DR: It is demonstrated that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets.
Abstract: Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application.
140 citations
TL;DR: An early endoderm gene expression signature is developed, and transcriptional similarities and differences between definitive and visceral endODerm are clarified, and methods for flow cytometric isolation of definitive and abdominal endoderman are developed.
133 citations
TL;DR: Although the biological methodology in Sjöblom et al. is sound, more samples are needed to achieve sufficient power, and few genes with significantly elevated mutation rates remain.
Abstract: Sjoblom et al (Research Article, 13 October 2006, p 268) reported nearly 200 novel cancer genes said to have a 90% probability of being involved in colon or breast cancer However, their analysis raises two statistical concerns When these concerns are addressed, few genes with significantly elevated mutation rates remain Although the biological methodology in Sjoblom et al is sound, more samples are needed to achieve sufficient power
129 citations
TL;DR: It is found that overexpression of miR-128a and b in ALL was at least partly associated with hypomethylation, rather than amplification of DNA locus copy, which will enhance the understanding of the biological role of these miRNAs and their targets in leukemogenesis, and in determining the lineage fate of acute leukemia.
125 citations
TL;DR: It is concluded that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment, and gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management.
TL;DR: The feasibility of a potentially high-throughput methodology combining automated in situ hybridization with quantum dot-labeled oligonucleotide probes followed by spectral imaging for the detection and subsequent deconvolution of multiple signals is demonstrated.
TL;DR: It is reported here that haploinsufficiency of the ribosomal protein encoding RPS14 gene causes the characteristic hematologic phenotype that defines the 5q- syndrome, and systematic RNA interference (RNAi) is used to interrogate the function of each gene in the common deleted region.
Patent•
30 Mar 2007TL;DR: Based on the discovery that celastrol and gedunin are Hsp90 inhibitors, the present invention provides novel inhibitors of Hsp 90 as mentioned in this paper. But, it does not address the problem of drug availability.
Abstract: Based on the discovery that celastrol and gedunin are Hsp90 inhibitors, the present invention provides novel inhibitors of Hsp90. and pharmaceutically acceptable salts,, derivatives, and compositions thereof. The invention provides two classes of compounds. One class includes celastrol and its derivatives. The other class includes gedunin and its derivatives. The present invention further provides methods for treating disorders wherein Hsρ90 inhibition is desired (e.g., proliferative diseases, cancer, inflammatory diseases, fungal infections, etc.) comprising administering a therapeutically effective amount of an inventive compound to a subject in need thereof. Celastrol, gedunin, and derivatives thereof are particularly useful in the treatment of prostate cancer, breast cancer, ovarian cancer, lung cancer, and leukemia.
TL;DR: A proteomics method identifies Spleen tyrosine kinase (Syk) as a strong candidate target of gefitinib, demonstrates that inhibition of Syk can induce AML differentiation, and identifies Syk as a potential target for AML differentiate therapy.
TL;DR: In multiple human prostate expression data set, it was found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy, suggesting that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease.
Abstract: Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease.
TL;DR: The concept that acquired mutations in cancer may not contribute to malignant transformation is supported and the importance of functional validation of candidate alleles discovered using high-throughput genomic screens is underscored to distinguish between ‘driver’ mutations underlying cancer development, and biologically neutral ‘passenger’ alterations.
TL;DR: Genomic characterization of a type of leukaemia has resulted in the identification of common genetic abnormalities that underlie the disease and constitutes an advance on several fronts.
Abstract: Genomic characterization of a type of leukaemia has resulted in the identification of common genetic abnormalities that underlie the disease. The results constitute an advance on several fronts.
TL;DR: The results suggest that type II and III NPC have not originated from obviously distinct epithelial precursors; rather, the histologic differences may be a consequence of a differential antiviral response, involving IFNs, to chronic EBV infection.
Abstract: Nonkeratinizing nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr Virus (EBV) and divided into two subtypes (WHO types II and III) based on histology. We tested whether these subtypes can be distinguished at the molecular genetic level using an algorithm that analyzes sets of related genes (gene set enrichment analysis). We found that a class of IFN-stimulated genes (ISG), frequently associated with the antiviral response, was significantly activated in type III versus type II NPC. Consistent with this, replication of the endogenous EBV was suppressed in type III. A strong association was also seen with a subset of ISGs previously identified in systemic lupus erythematosus, another disease in which 'normal' EBV biology is deregulated, suggesting that this pattern of ISG expression may be linked to the increased EBV activity in both diseases. In contrast, unsupervised hierarchical clustering of the complete expression profiles failed to distinguish the two subsets. These results suggest that type II and III NPC have not originated from obviously distinct epithelial precursors; rather, the histologic differences may be a consequence of a differential antiviral response, involving IFNs, to chronic EBV infection.