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Publication
Journal: Nature
September/17/2009
Abstract
MicroRNAs (miRNAs) are regulators of myriad cellular events, but evidence for a single miRNA that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct reprogramming of cells into an alternative cell fate has been elusive. Here we show that miR-<em>1</em>45 and miR-<em>1</em>43 are co-transcribed in multipotent murine cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem-cell-derived vascular smooth muscle cells. miR-<em>1</em>45 and miR-<em>1</em>43 were direct transcriptional targets of serum response factor, myocardin and <em>Nkx2</em>-5 (NK2 transcription factor related, locus 5) and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-<em>1</em>45 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-<em>1</em>45 and miR-<em>1</em>43 cooperatively targeted a network of transcription factors, including Klf4 (Kruppel-like factor 4), myocardin and Elk-<em>1</em> (ELK<em>1</em>, member of ETS oncogene family), to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-<em>1</em>45 can direct the smooth muscle fate and that miR-<em>1</em>45 and miR-<em>1</em>43 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.
Publication
Journal: Nature
January/10/2008
Abstract
Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 37<em>1</em>) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 3<em>1</em> recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome <em>1</em>4q<em>1</em>3.3, is found in approximately <em>1</em>2% of samples. On the basis of genomic and functional analyses, we identify <em>NKX2</em>-<em>1</em> (NK2 homeobox <em>1</em>, also called TITF<em>1</em>), which lies in the minimal <em>1</em>4q<em>1</em>3.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
Publication
Journal: Nature
March/20/2016
Abstract
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into <em>1</em>0 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G<em>1</em>/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (<em>1</em>) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX<em>1</em> and MNX<em>1</em>). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD<em>1</em> and <em>NKX2</em>-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publication
Journal: Nature
July/10/2008
Abstract
The heart is formed from cardiogenic progenitors expressing the transcription factors <em>Nkx2</em>-5 and Isl<em>1</em> (refs <em>1</em> and 2). These multipotent progenitors give rise to cardiomyocyte, smooth muscle and endothelial cells, the major lineages of the mature heart. Here we identify a novel cardiogenic precursor marked by expression of the transcription factor Wt<em>1</em> and located within the epicardium-an epithelial sheet overlying the heart. During normal murine heart development, a subset of these Wt<em>1</em>(+) precursors differentiated into fully functional cardiomyocytes. Wt<em>1</em>(+) proepicardial cells arose from progenitors that express <em>Nkx2</em>-5 and Isl<em>1</em>, suggesting that they share a developmental origin with multipotent <em>Nkx2</em>-5(+) and Isl<em>1</em>(+) progenitors. These results identify Wt<em>1</em>(+) epicardial cells as previously unrecognized cardiomyocyte progenitors, and lay the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair.
Publication
Journal: Development (Cambridge)
April/26/1999
Abstract
Csx/<em>Nkx2</em>.5 is a vertebrate homeobox gene with a sequence homology to the Drosophila tinman, which is required for the dorsal mesoderm specification. Recently, heterozygous mutations of this gene were found to cause human congenital heart disease (Schott, J.-J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E. and Seidman, J. G. (<em>1</em>998) Science 28<em>1</em>, <em>1</em>08-<em>1</em><em>1</em><em>1</em>). To investigate the functions of Csx/<em>Nkx2</em>.5 in cardiac and extracardiac development in the vertebrate, we have generated and analyzed mutant mice completely null for Csx/<em>Nkx2</em>.5. Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels. Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac. Interestingly, TUNEL staining and PCNA staining showed neither enhanced apoptosis nor reduced cell proliferation in the mutant myocardium. In situ hybridization studies demonstrated that, among 20 candidate genes examined, expression of ANF, BNP, MLC2V, N-myc, MEF2C, HAND<em>1</em> and Msx2 was disturbed in the mutant heart. Moreover, in the heart of adult chimeric mice generated from Csx/<em>Nkx2</em>.5 null ES cells, there were almost no ES cell-derived cardiac myocytes, while there were substantial contributions of Csx /<em>Nkx2</em>.5-deficient cells in other organs. Whole-mount &bgr;-gal staining of chimeric embryos showed that more than 20% contribution of Csx/<em>Nkx2</em>. 5-deficient cells in the heart arrested cardiac development. These results indicate that (<em>1</em>) the complete null mutation of Csx/<em>Nkx2</em>.5 did not abolish initial heart looping, (2) there was no enhanced apoptosis or defective cell cycle entry in Csx/<em>Nkx2</em>.5 null cardiac myocytes, (3) Csx/<em>Nkx2</em>.5 regulates expression of several essential transcription factors in the developing heart, (4) Csx/<em>Nkx2</em>.5 is required for later differentiation of cardiac myocytes, (5) Csx/<em>Nkx2</em>. 5 null cells exert dominant interfering effects on cardiac development, and (6) there were severe defects in yolk sac angiogenesis and hematopoiesis in the Csx/<em>Nkx2</em>.5 null embryos.
Publication
Journal: Cell Metabolism
March/20/2014
Abstract
The mammalian Sir2 ortholog Sirt<em>1</em> plays an important role in metabolic regulation. However, the role of Sirt<em>1</em> in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt<em>1</em>-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox <em>1</em> (<em>Nkx2</em>-<em>1</em>) as a partner of Sirt<em>1</em> that upregulates Ox2r transcription and colocalizes with Sirt<em>1</em> in the DMH and LH. DMH/LH-specific knockdown of Sirt<em>1</em>, <em>Nkx2</em>-<em>1</em>, or Ox2r and DMH-specific Sirt<em>1</em> overexpression further support the role of Sirt<em>1</em>/<em>Nkx2</em>-<em>1</em>/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt<em>1</em> activity in the regulation of aging and longevity in mammals.
Publication
Journal: Nature
May/9/2011
Abstract
Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G<em>1</em>2D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor <em>Nkx2</em>-<em>1</em> (also called Ttf-<em>1</em> or Titf<em>1</em>) as a candidate suppressor of malignant progression. In this mouse model, <em>Nkx2</em>-<em>1</em> negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that <em>Nkx2</em>-<em>1</em> controls tumour differentiation and limits metastatic potential in vivo. Interrogation of <em>Nkx2</em>-<em>1</em>-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that <em>Nkx2</em>-<em>1</em> constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of <em>NKX2</em>-<em>1</em> in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link <em>Nkx2</em>-<em>1</em> downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of <em>Nkx2</em>-<em>1</em> in the same tumour type substantiate its role as a dual function lineage factor.
Publication
Journal: Nature Genetics
May/13/2009
Abstract
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in <em>1</em>92 and 37,<em>1</em>96 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and <em>1</em>4q<em>1</em>3.3, are associated with the disease. Overall, the strongest association signals were observed for rs9655<em>1</em>3 on 9q22.33 (OR = <em>1</em>.75; P = <em>1</em>.7 x <em>1</em>0(-27)) and rs944289 on <em>1</em>4q<em>1</em>3.3 (OR = <em>1</em>.37; P = 2.0 x <em>1</em>0(-9)). The gene nearest to the 9q22.33 locus is FOXE<em>1</em> (TTF2) and <em>NKX2</em>-<em>1</em> (TTF<em>1</em>) is among the genes located at the <em>1</em>4q<em>1</em>3.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
Publication
Journal: Nature
September/1/2009
Abstract
Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals. In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription; however, the control mechanisms and functions of H3K36me3 in higher eukaryotes are unknown. Here we show that the H3K36me3-specific histone methyltransferase (HMTase) Wolf-Hirschhorn syndrome candidate <em>1</em> (WHSC<em>1</em>, also known as NSD2 or MMSET) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). We found that mouse Whsc<em>1</em>, one of five putative Set2 homologues, governed H3K36me3 along euchromatin by associating with the cell-type-specific transcription factors Sall<em>1</em>, Sall4 and Nanog in embryonic stem cells, and <em>Nkx2</em>-5 in embryonic hearts, regulating the expression of their target genes. Whsc<em>1</em>-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc<em>1</em> haploinsufficiency were increased in <em>Nkx2</em>-5 heterozygous mutant hearts, indicating their functional link. We propose that WHSC<em>1</em> functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.
Publication
Journal: Cancer Discovery
May/4/2016
Abstract
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in STK<em>1</em><em>1</em>/LKB<em>1</em> (the KL subgroup), TP53 (KP), and CDKN2A/B inactivation coupled with low expression of the <em>NKX2</em>-<em>1</em> (TTF<em>1</em>) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC<em>1</em> signaling. KL tumors had high rates of KEAP<em>1</em> mutational inactivation and expressed lower levels of immune markers, including PD-L<em>1</em>. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.
CONCLUSIONS
Co-occurring genetic alterations in STK<em>1</em><em>1</em>/LKB<em>1</em>, TP53, and CDKN2A/B-the latter coupled with low TTF<em>1</em> expression-define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities.
Publication
Journal: Neuron
October/22/2008
Abstract
Previous work has demonstrated that the character of mouse cortical interneuron subtypes can be directly related to their embryonic temporal and spatial origins. The relationship between embryonic origin and the character of mature interneurons is likely reflected by the developmental expression of genes that direct cell fate. However, a thorough understanding of the early genetic events that specify subtype identity has been hampered by the perinatal lethality resulting from the loss of genes implicated in the determination of cortical interneurons. Here, we employ a conditional loss-of-function approach to demonstrate that the transcription factor <em>Nkx2</em>-<em>1</em> is required for the proper specification of specific interneuron subtypes. Removal of this gene at distinct neurogenic time points results in a switch in the subtypes of neurons observed at more mature ages. Our strategy reveals a causal link between the embryonic genetic specification by <em>Nkx2</em>-<em>1</em> in progenitors and the functional attributes of their neuronal progeny in the mature nervous system.
Publication
Journal: Cell Stem Cell
July/2/2012
Abstract
Two populations of <em>Nkx2</em>-<em>1</em>(+) progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using <em>Nkx2</em>-<em>1</em>(GFP) knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.
Publication
Journal: Cancer Cell
June/6/2011
Abstract
To identify oncogenic pathways in T cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of <em>1</em><em>1</em>7 pediatric patient samples and detailed molecular-cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes, and ectopic <em>NKX2</em>-<em>1</em> or <em>NKX2</em>-2 expression for which rearrangements were identified. The second subtype associated with immature T cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C, or MEF2C-associated cofactors. We propose <em>NKX2</em>-<em>1</em>, <em>NKX2</em>-2, and MEF2C as T-ALL oncogenes that are activated by various rearrangements.
Publication
Journal: Developmental Biology
May/31/1999
Abstract
NKX2.<em>1</em> is a homeodomain transcriptional factor expressed in thyroid, lung, and parts of the brain. We demonstrate that septation of the anterior foregut along the dorsoventral axis, into distinct tracheal and esophageal structures, is blocked in mouse embryos carrying a homozygous targeted disruption of the <em>Nkx2</em>.<em>1</em> locus. This is consistent with the loss of <em>Nkx2</em>.<em>1</em> expression, which defines the dorsoventral boundary within the anterior foregut in wild-type E9 embryos. Failure in septation between the trachea and the esophagus in <em>Nkx2</em>.<em>1</em>(-/-) mice leads to the formation of a common lumen that connects the pharynx to the stomach, serving both as trachea and as esophagus, similar in phenotype to a human pathologic condition termed tracheoesophageal fistula. The main-stem bronchi bifurcate from this common structure and connect to profoundly hypoplastic lungs. The mutant lungs fail to undergo normal branching embryogenesis, consist of highly dilated sacs that are not capable of sustaining normal gas exchange functions, and lead to immediate postnatal death. In situ hybridization suggests reduced Bmp-4 expression in the mutant lung epithelium, providing a possible mechanistic clue for impaired branching. Functional deletion of <em>Nkx2</em>. <em>1</em> blocks pulmonary-specific epithelial cell differentiation marked by the absence of pulmonary surfactant protein gene expression. Altered expression of temporally regulated genes such as Vegf demonstrates that the lung in <em>Nkx2</em>.<em>1</em>(-/-) mutant embryos is arrested at early pseudoglandular (E<em>1</em><em>1</em>-E<em>1</em>5) stage. These results demonstrate a critical role for <em>Nkx2</em>.<em>1</em> in morphogenesis of the anterior foregut and the lung as well as in differentiation of pulmonary epithelial cells.
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Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
December/12/2007
Abstract
We used high-resolution array analysis to discover a recurrent lung cancer amplicon located at <em>1</em>4q<em>1</em>3.3. Low-level gain of this region was detected in <em>1</em>5% of lung cancer samples, and high-level amplification was detected in an additional 4% of samples. High-level focal amplification appears to be specific to lung cancers, because it was not detected in >500 samples of other tumor types. Mapping of the commonly amplified region revealed there are three genes in the core region, all of which encode transcription factors with either established lung developmental function (TTF<em>1</em>/<em>NKX2</em>-<em>1</em>, <em>NKX2</em>-8) or potential lung developmental function (PAX9). All three genes were overexpressed to varying degrees in amplified samples, although TTF<em>1</em>/<em>NKX2</em>-<em>1</em> was not expressed in the squamous cancer subtype, consistent with previous reports. Remarkably, overexpression of any pairwise combination of these genes showed pronounced synergy in promoting the proliferation of immortalized human lung epithelial cells. Analysis of human lung cancer cell lines by both RNAi and ectopic overexpression further substantiates an oncogenic role for these transcription factors. These results, taken together with previous reports of oncogenic alterations of transcription factors involved in lung development (p63, CEBPA), suggest genetic alterations that directly interfere with transcriptional networks normally regulating lung development may be a more common feature of lung cancer than previously realized.
Publication
Journal: Oncogene
June/23/2008
Abstract
Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of <em>1</em>28 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband <em>1</em>4q<em>1</em>3.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF<em>1</em> (thyroid transcription factor <em>1</em>; also called <em>NKX2</em>-<em>1</em>), previously linked to normal lung development and function. When amplified, TITF<em>1</em> exhibited increased expression at both the RNA and protein levels. Small interfering RNA (siRNA)-mediated knockdown of TITF<em>1</em> in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF<em>1</em> amplification and overexpression contribute to lung cancer cell proliferation rates and survival and implicate TITF<em>1</em> as a lineage-specific oncogene in lung cancer.
Publication
Journal: Nature Genetics
September/22/1999
Abstract
In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx<em>1</em>, Isl<em>1</em>, Pax4, Pax6 and <em>Nkx2</em>-2 (refs 3,4,5,6,7, 8,9,<em>1</em>0). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature beta-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9-/- pancreas has small islets of Langerhans with reduced numbers of insulin-producing beta-cells. Hlxb9-/- beta-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-<em>1</em>. Thus, Hlxb9 is key to normal pancreas development and function.
Publication
Journal: Neoplasia
May/5/2008
Abstract
A recurrent gene fusion between EML4 and ALK in 6.7% of non-small cell lung cancers (NSCLCs) and <em>NKX2</em>-<em>1</em> (TTF<em>1</em>, TITF<em>1</em>) high-level amplifications in <em>1</em>2% of adenocarcinomas of the lung were independently reported recently. Because the EML4-ALK fusion was only shown by a reverse transcription-polymerase chain reaction approach, we developed fluorescent in situ hybridization assays to interrogate more than 600 NSCLCs using break-apart probes for EML4 and ALK. We found that EML4-ALK fusions occur in less than 3% of NSCLC samples and that EML4 and/or ALK amplifications also occur. We also observed that, in most cases in which an EML4/ALK alteration is detected, not all of the tumor cells harbor the lesion. By using a detailed multi-fluorescent in situ hybridization probe assay and reverse transcription-polymerase chain reaction, we have evidence that other, more common mechanisms besides gene inversion exist including the possibility of other fusion partners for ALK and EML4. Furthermore, we confirmed the <em>NKX2</em>-<em>1</em> high-level amplification in a significant subset of NSCLC and found this amplification to be mutually exclusive to ALK and EML4 rearrangements.
Publication
Journal: Cancer Cell
June/17/2012
Abstract
We and others previously identified <em>NKX2</em>-<em>1</em>, also known as TITF<em>1</em> and TTF-<em>1</em>, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that <em>NKX2</em>-<em>1</em> induces the expression of the receptor tyrosine kinase-like orphan receptor <em>1</em> (ROR<em>1</em>), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR<em>1</em> kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR<em>1</em> knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR<em>1</em> as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.
Publication
Journal: Nature
December/25/2012
Abstract
The primary function of the thyroid gland is to metabolize iodide by synthesizing thyroid hormones, which are critical regulators of growth, development and metabolism in almost all tissues. So far, research on thyroid morphogenesis has been missing an efficient stem-cell model system that allows for the in vitro recapitulation of the molecular and morphogenic events regulating thyroid follicular-cell differentiation and subsequent assembly into functional thyroid follicles. Here we report that a transient overexpression of the transcription factors <em>NKX2</em>-<em>1</em> and PAX8 is sufficient to direct mouse embryonic stem-cell differentiation into thyroid follicular cells that organize into three-dimensional follicular structures when treated with thyrotropin. These in vitro-derived follicles showed appreciable iodide organification activity. Importantly, when grafted in vivo into athyroid mice, these follicles rescued thyroid hormone plasma levels and promoted subsequent symptomatic recovery. Thus, mouse embryonic stem cells can be induced to differentiate into thyroid follicular cells in vitro and generate functional thyroid tissue.
Publication
Journal: Journal of Clinical Investigation
March/20/2002
Abstract
The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene <em>Nkx2</em>-<em>1</em>, we investigated the human <em>NKX2</em>-<em>1</em> gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C25<em>1</em>9A, C<em>1</em>302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the <em>NKX2</em>-<em>1</em> gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with <em>NKX2</em>-<em>1</em> mutations points to an important role of human <em>NKX2</em>-<em>1</em> in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
Publication
Journal: Neuron
October/22/2008
Abstract
The homeodomain transcription factor <em>Nkx2</em>-<em>1</em> plays key roles in the developing telencephalon, where it regulates the identity of progenitor cells in the medial ganglionic eminence (MGE) and mediates the specification of several classes of GABAergic and cholinergic neurons. Here, we have investigated the postmitotic function of <em>Nkx2</em>-<em>1</em> in the migration of interneurons originating in the MGE. Experimental manipulations and mouse genetics show that downregulation of <em>Nkx2</em>-<em>1</em> expression in postmitotic cells is necessary for the migration of interneurons to the cortex, whereas maintenance of <em>Nkx2</em>-<em>1</em> expression is required for interneuron migration to the striatum. <em>Nkx2</em>-<em>1</em> exerts this role in the migration of MGE-derived interneurons by directly regulating the expression of a guidance receptor, Neuropilin-2, which enables interneurons to invade the developing striatum. Our results demonstrate a role for the cell-fate determinant <em>Nkx2</em>-<em>1</em> in regulating neuronal migration by direct transcriptional regulation of guidance receptors in postmitotic cells.
Publication
Journal: Circulation
April/19/2011
Abstract
BACKGROUND
Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration.
RESULTS
Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, <30 days), infants (age, <em>1</em> month to 2 years), and children (age, >2 to ≤<em>1</em>3 years). C-kit(+) hCPCs were 3-fold higher in neonates than in children >2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit(+) Ki67(+) expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit(+), <em>NKX2</em>-5(+), NOTCH<em>1</em>(+), and NUMB(+) expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium-derived CPCs from all patients (n=<em>1</em>03) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit(+), Islet-<em>1</em>, and supporting cells. The number of c-kit(+)-expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts.
CONCLUSIONS
Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair.
Publication
Journal: Clinical Cancer Research
September/22/2013
Abstract
OBJECTIVE
Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC.
METHODS
An <em>1</em>8-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The <em>1</em>8-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a <em>1</em>2-gene predictive signature for ACT benefits in NSCLC.
RESULTS
Using a cohort of 442 stage I to III NSCLC patients who underwent surgical resection, we identified an <em>1</em>8-hub-gene set that robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including <em>NKX2</em>-<em>1</em>, Aurora Kinase A, PRC<em>1</em>, CDKN3, MBIP, and RRM2. The <em>1</em>2-gene predictive signature was successfully validated in two independent datasets (n = 90 and <em>1</em>76). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: HR = 0.34, P = 0.0<em>1</em>7; JBR.<em>1</em>0 clinical trial data: HR = 0.36, P = 0.038), whereas the predicted nonbenefit group showed no survival benefit for 2 datasets (HR = 0.80, P = 0.70; HR = 0.9<em>1</em>, P = 0.82).
CONCLUSIONS
This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small cell lung cancer will have a survival benefit with ACT.
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