POLE

Gene Summary

Gene:POLE; polymerase (DNA directed), epsilon, catalytic subunit
Aliases: FILS, POLE1, CRCS12
Location:12q24.3
Summary:This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:DNA polymerase epsilon catalytic subunit A
HPRD
Source:NCBIAccessed: 26 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 26 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: POLE (cancer-related)

Sistigu A, Yamazaki T, Vacchelli E, et al.
Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy.
Nat Med. 2014; 20(11):1301-9 [PubMed] Related Publications
Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.

Sirintrapun SJ, Geisinger KR, Cimic A, et al.
Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization.
Medicine (Baltimore). 2014; 93(15):e81 [PubMed] Related Publications
Renal oncocytoma is a benign tumor with characteristic histologic findings. We describe an oncocytoma-like renal tumor with progression to high-grade oncocytic carcinoma and metastasis. A 74-year-old man with no family history of cancer presented with hematuria. Computed tomography showed an 11 cm heterogeneous multilobulated mass in the right kidney lower pole, enlarged aortocaval lymph nodes, and multiple lung nodules. In the nephrectomy specimen, approximately one third of the renal tumor histologically showed regions classic for benign oncocytoma transitioning to regions of high-grade carcinoma without sharp demarcation. With extensive genomic investigation using single nucleotide polymorphism-based array virtual karyotyping, multiregion sequencing, and expression array analysis, we were able to show a common lineage between the benign oncocytoma and high-grade oncocytic carcinoma regions in the tumor. We were also able to show karyotypic differences underlying this progression. The benign oncocytoma showed no chromosomal aberrations, whereas the high-grade oncocytic carcinoma showed loss of the 17p region housing FLCN (folliculin [Birt-Hogg-Dubé protein]), loss of 8p, and gain of 8q. Gene expression patterns supported dysregulation and activation of phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathways in the high-grade oncocytic carcinoma regions. This was partly attributable to FLCN underexpression but further accentuated by overexpression of numerous genes on 8q. In the high-grade oncocytic carcinoma region, vascular endothelial growth factor A along with metalloproteinases matrix metallopeptidase 9 and matrix metallopeptidase 12 were overexpressed, facilitating angiogenesis and invasiveness. Genetic molecular testing provided evidence for the development of an aggressive oncocytic carcinoma from an oncocytoma, leading to aggressive targeted treatment but eventual death 39 months after the diagnosis.

Haraldsdottir S, Hampel H, Tomsic J, et al.
Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
Gastroenterology. 2014; 147(6):1308-1316.e1 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND & AIMS: Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing.
METHODS: We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established.
RESULTS: Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase.
CONCLUSIONS: Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.

Nault JC, Calderaro J, Di Tommaso L, et al.
Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.
Hepatology. 2014; 60(6):1983-92 [PubMed] Related Publications
UNLABELLED: Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC.
CONCLUSION: Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC.

Roy T, Barman S
A behavioral study of healthy and cancer genes by modeling electrical network.
Gene. 2014; 550(1):81-92 [PubMed] Related Publications
In recent years, gene network modeling is gaining popularity in genomics to monitor the activity profile of genes. More specifically, the objective of the network modeling concept is to study the genetic behavior associated with disease. Previous researchers have designed network model at nucleotide level which produces more complexity for designing circuits mostly in case of gene expression studies. Whereas the authors have designed the present network model, based on amino acid level which is simpler as well as more appropriate for prediction of the genetic abnormality. In the present concept, SISO continuous and discrete system models of genes are realized using Foster network. The model is designed based on hydropathy index value of amino acids to study the biological system behavior. The time and phase response in continuous (s) domain and pole-zero distribution in discrete (z) domain are used as measurement metric in the present study. The simulated responses of the system show genetic instability for cancer genes which truly reflects the medical reports. The proposed modeling concept can be used, to accurately identify or separate out the diseased genes from healthy genes.

Michels J, Obrist F, Vitale I, et al.
MCL-1 dependency of cisplatin-resistant cancer cells.
Biochem Pharmacol. 2014; 92(1):55-61 [PubMed] Related Publications
The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings.

Henninger EE, Pursell ZF
DNA polymerase ε and its roles in genome stability.
IUBMB Life. 2014; 66(5):339-51 [PubMed] Related Publications
DNA Polymerase Epsilon (Pol ε) is one of three DNA Polymerases (along with Pol δ and Pol α) required for nuclear DNA replication in eukaryotes. Pol ε is comprised of four subunits, the largest of which is encoded by the POLE gene and contains the catalytic polymerase and exonuclease activities. The 3'-5' exonuclease proofreading activity is able to correct DNA synthesis errors and helps protect against genome instability. Recent cancer genome sequencing efforts have shown that 3% of colorectal and 7% of endometrial cancers contain mutations within the exonuclease domain of POLE and are associated with significantly elevated levels of single nucleotide substitutions (15-500 per Mb) and microsatellite stability. POLE mutations have also been found in other tumor types, though at lower frequency, suggesting roles in tumorigenesis more broadly in different tissue types. In addition to its proofreading activity, Pol ε contributes to genome stability through multiple mechanisms that are discussed in this review.

Brégeon F, Brioude G, De Dominicis F, et al.
MALDI-ToF mass spectrometry for the rapid diagnosis of cancerous lung nodules.
PLoS One. 2014; 9(5):e97511 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Recently, tissue-based methods for proteomic analysis have been used in clinical research and appear reliable for digestive, brain, lymphomatous, and lung cancers classification. However simple, tissue-based methods that couple signal analysis to tissue imaging are time consuming. To assess the reliability of a method involving rapid tissue preparation and analysis to discriminate cancerous from non-cancerous tissues, we tested 141 lung cancer/non-tumor pairs and 8 unique lung cancer samples among the stored frozen samples of 138 patients operated on during 2012. Samples were crushed in water, and 1.5 µl was spotted onto a steel target for analysis with the Microflex LT analyzer (Bruker Daltonics). Spectra were analyzed using ClinProTools software. A set of samples was used to generate a random classification model on the basis of a list of discriminant peaks sorted with the k-nearest neighbor genetic algorithm. The rest of the samples (n = 43 cancerous and n = 41 non-tumoral) was used to verify the classification capability and calculate the diagnostic performance indices relative to the histological diagnosis. The analysis found 53 m/z valid peaks, 40 of which were significantly different between cancerous and non-tumoral samples. The selected genetic algorithm model identified 20 potential peaks from the training set and had 98.81% recognition capability and 89.17% positive predictive value. In the blinded set, this method accurately discriminated the two classes with a sensitivity of 86.7% and a specificity of 95.1% for the cancer tissues and a sensitivity of 87.8% and a specificity of 95.3% for the non-tumor tissues. The second model generated to discriminate primary lung cancer from metastases was of lower quality. The reliability of MALDI-ToF analysis coupled with a very simple lung preparation procedure appears promising and should be tested in the operating room on fresh samples coupled with the pathological examination.

Rohlin A, Zagoras T, Nilsson S, et al.
A mutation in POLE predisposing to a multi-tumour phenotype.
Int J Oncol. 2014; 45(1):77-81 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase ε have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra-colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers.

Quintin J, Le Péron C, Palierne G, et al.
Dynamic estrogen receptor interactomes control estrogen-responsive trefoil Factor (TFF) locus cell-specific activities.
Mol Cell Biol. 2014; 34(13):2418-36 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Estradiol signaling is ideally suited for analyzing the molecular and functional linkages between the different layers of information directing transcriptional regulations: the DNA sequence, chromatin modifications, and the spatial organization of the genome. Hence, the estrogen receptor (ER) can bind at a distance from its target genes and engages timely and spatially coordinated processes to regulate their expression. In the context of the coordinated regulation of colinear genes, identifying which ER binding sites (ERBSs) regulate a given gene still remains a challenge. Here, we investigated the coordination of such regulatory events at a 2-Mb genomic locus containing the estrogen-sensitive trefoil factor (TFF) cluster of genes in breast cancer cells. We demonstrate that this locus exhibits a hormone- and cohesin-dependent reduction in the plasticity of its three-dimensional organization that allows multiple ERBSs to be dynamically brought to the vicinity of estrogen-sensitive genes. Additionally, by using triplex-forming oligonucleotides, we could precisely document the functional links between ER engagement at given ERBSs and the regulation of particular genes. Hence, our data provide evidence of a formerly suggested cooperation of enhancers toward gene regulation and also show that redundancy between ERBSs can occur.

Glorieux C, Auquier J, Dejeans N, et al.
Catalase expression in MCF-7 breast cancer cells is mainly controlled by PI3K/Akt/mTor signaling pathway.
Biochem Pharmacol. 2014; 89(2):217-23 [PubMed] Related Publications
Catalase is an antioxidant enzyme that catalyzes mainly the transformation of hydrogen peroxide into water and oxygen. Although catalase is frequently down-regulated in tumors the underlying mechanism remains unclear. Few transcription factors have been reported to directly bind the human catalase promoter. Among them FoxO3a has been proposed as a positive regulator of catalase expression. Therefore, we decided to study the role of the transcription factor FoxO3a and the phosphatidylinositol-3 kinase (PI3K) signaling pathway, which regulates FoxO3a, in the expression of catalase. To this end, we developed an experimental model of mammary breast MCF-7 cancer cells that acquire resistance to oxidative stress, the so-called Resox cells, in which catalase is overexpressed as compared with MCF-7 parental cell line. In Resox cells, Akt expression is decreased but its phosphorylation is enhanced when compared with MCF-7 cells. A similar profile is observed for FoxO3a, with less total protein but more phosphorylated FoxO3a in Resox cells, correlating with its higher Akt activity. The modulation of FoxO3a expression by knockdown and overexpression strategies did not affect catalase expression, neither in MCF-7 nor in Resox cells. Inhibition of PI3K and mTOR by LY295002 and rapamycin, respectively, decreases the phosphorylation of downstream targets (i.e. GSK3β and p70S6K) and leads to an increase of catalase expression only in MCF-7 but not in Resox cells. In conclusion, FoxO3a does not appear to play a critical role in the regulation of catalase expression in both cancer cells. Only MCF-7 cells are sensitive and dependent on PI3K/Akt/mTOR signaling.

Yang F, Xiong J, Jia XE, et al.
GSTT1 deletion is related to polycyclic aromatic hydrocarbons-induced DNA damage and lymphoma progression.
PLoS One. 2014; 9(2):e89302 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.

Jia P, Pao W, Zhao Z
Patterns and processes of somatic mutations in nine major cancers.
BMC Med Genomics. 2014; 7:11 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Cancer genomes harbor hundreds to thousands of somatic nonsynonymous mutations. DNA damage and deficiency of DNA repair systems are two major forces to cause somatic mutations, marking cancer genomes with specific somatic mutation patterns. Recently, several pan-cancer genome studies revealed more than 20 mutation signatures across multiple cancer types. However, detailed cancer-type specific mutation signatures and their different features within (intra-) and between (inter-) cancer types remain largely unexplored.
METHODS: We employed a matrix decomposition algorithm, namely Non-negative Matrix Factorization, to survey the somatic mutations in nine major human cancers, involving a total of ~2100 genomes.
RESULTS: Our results revealed 3-5 independent mutational signatures in each cancer, implying that a range of 3-5 predominant mutational processes likely underlie each cancer genome. Both mutagen exposure (tobacco and sun) and changes in DNA repair systems (APOBEC family, POLE, and MLH1) were found as mutagenesis forces, each of which marks the genome with an evident mutational signature. We studied the features of several signatures and their combinatory patterns within and across cancers. On one hand, we found each signature may influence a cancer genome with different influential magnitudes even in the same cancer type and the signature-specific load reflects intra-cancer heterogeneity (e.g., the smoking-related signature in lung cancer smokers and never smokers). On the other hand, inter-cancer heterogeneity is characterized by combinatory patterns of mutational signatures, where no cancers share the same signature profile, even between two lung cancer subtypes (lung adenocarcinoma and squamous cell lung cancer).
CONCLUSIONS: Our work provides a detailed overview of the mutational characteristics in each of nine major cancers and highlights that the mutational signature profile is representative of each cancer.

Zou Y, Liu FY, Liu H, et al.
Frequent POLE1 p.S297F mutation in Chinese patients with ovarian endometrioid carcinoma.
Mutat Res Fundam Mol Mech Mutagen. 2014; 761:49-52 [PubMed] Related Publications
The catalytic subunit of DNA polymerase epsilon (POLE1) functions primarily in nuclear DNA replication and repair. Recently, POLE1 mutations were detected frequently in colorectal and endometrial carcinomas while with lower frequency in several other types of cancer, and the p.P286R and p.V411L mutations were the potential mutation hotspots in human cancers. Nevertheless, the mutation frequency of POLE1 in ovarian cancer still remains largely unknown. Here, we screened a total of 251 Chinese samples with distinct subtypes of ovarian carcinoma for the presence of POLE1 hotspot mutations by direct sequencing. A heterozygous somatic POLE1 mutation, p.S297F (c.890C>T), but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was identified in 3 out of 37 (8.1%) patients with ovarian endometrioid carcinoma; this mutation was evolutionarily highly conserved from Homo sapiens to Schizosaccharomyces. Of note, the POLE1 mutation coexisted with mutation in the ovarian cancer-associated PPP2R1A (protein phosphatase 2, regulatory subunit A, α) gene in a 46-year-old patient, who was also diagnosed with ectopic endometriosis in the benign ovary. In addition, a 45-year-old POLE1-mutated ovarian endometrioid carcinoma patient was also diagnosed with uterine leiomyoma while the remaining 52-year-old POLE1-mutated patient showed no additional distinctive clinical manifestation. In contrast to high frequency of POLE1 mutations in ovarian endometrioid carcinoma, no POLE1 mutations were identified in patients with other subtypes of ovarian carcinoma. Our results showed for the first time that the POLE1 p.S297F mutation, but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was frequent in Chinese ovarian endometrioid carcinoma, but absent in other subtypes of ovarian carcinoma. These results implicated that POLE1 p.S297F mutation might be actively involved in the pathogenesis of ovarian endometrioid carcinoma, but might not be actively involved in other subtypes of ovarian carcinoma.

Tufo G, Jones AW, Wang Z, et al.
The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.
Cell Death Differ. 2014; 21(5):685-95 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

Lelièvre SA, Weaver CM
Global nutrition research: nutrition and breast cancer prevention as a model.
Nutr Rev. 2013; 71(11):742-52 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The gene-environment interaction is paramount in light of the worldwide rise in incidence of chronic diseases, with cancers in the pole position. Diet is an environmental factor with potential to influence cancer onset by shaping the epigenome (i.e., the genome organization that controls the differential expression of genes). Yet, there is no consensus regarding how diet might help prevent breast cancer, the second most frequent malignancy globally. The complexity of breast cancers requires working on a global and multidisciplinary scale to further understand the relationship between breast cancer type, diet, and the epigenome. This article describes the International Breast Cancer & Nutrition collaboration as one such approach. A global endeavor brings the diversity necessary to pinpoint important diet-gene relationships. Being developed are models, detection and assessment tools, and funding and public policy frameworks necessary to advance primary prevention research for the benefit of all populations affected by breast cancer. This paradigm can be adapted to understanding diet-gene relationships for other chronic diseases.

Leboeuf C, Mailly L, Wu T, et al.
In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.
Mol Ther. 2014; 22(3):634-44 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Cell therapy based on alloreactivity has completed clinical proof of concept against hematological malignancies. However, the efficacy of alloreactivity as a therapeutic approach to treat solid tumors is unknown. Using cell culture and animal models, we aimed to investigate the efficacy and safety of allogeneic suicide gene-modified killer cells as a cell-based therapy for hepatocellular carcinoma (HCC), for which treatment options are limited. Allogeneic killer cells from healthy donors were isolated, expanded, and phenotypically characterized. Antitumor cytotoxic activity and safety were studied using a panel of human or murine HCC cell lines engrafted in immunodeficient or immunocompetent mouse models. Human allogeneic suicide gene-modified killer cells (aSGMKCs) exhibit a high, rapid, interleukin-2-dependent, and non-major histocompatibility complex class I-restricted in vitro cytotoxicity toward human hepatoma cells, mainly mediated by natural killer (NK) and NK-like T cells. In vivo evaluation of this cell therapy product demonstrates a marked, rapid, and sustained regression of HCC. Preferential liver homing of effector cells contributed to its marked efficacy. Calcineurin inhibitors allowed preventing rejection of allogeneic lymphocytes by the host immune system without impairing their antitumor activity. Our results demonstrate proof of concept for aSGMKCs as immunotherapy for HCC and open perspectives for the clinical development of this approach.

Gnemmi V, Bouillez A, Gaudelot K, et al.
MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/β-catenin pathway and interaction with SNAIL promoter.
Cancer Lett. 2014; 346(2):225-36 [PubMed] Related Publications
MUC1 is overexpressed in human carcinomas. The transcription factor SNAIL can activate epithelial-mesenchymal transition (EMT) in cancer cells. In this study, in renal carcinoma, we demonstrate that (i) MUC1 and SNAIL were overexpressed in human sarcomatoid carcinomas, (ii) SNAIL increased indirectly MUC1 expression, (iii) MUC1 overexpression induced EMT, (iv) MUC1 C-terminal domain (MUC1-C) and β-catenin increased SNAIL transcriptional activity by interaction with its promoter and (v) blocking MUC1-C nuclear localization decreased Wnt/β-catenin signaling pathway activation and SNAIL expression. Altogether, our findings demonstrate that MUC1 is an actor in EMT and appears as a new therapeutic target.

Mescam-Mancini L, Lantuéjoul S, Moro-Sibilot D, et al.
On the relevance of a testing algorithm for the detection of ROS1-rearranged lung adenocarcinomas.
Lung Cancer. 2014; 83(2):168-73 [PubMed] Related Publications
OBJECTIVES: ROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. These rearrangements are described in 0.9-1.7% NSCLC, in wild-type EGFR, KRAS and ALK ("triple negative") lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important.
MATERIALS AND METHODS: In this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR, KRAS, PI3KCA, BRAF, HER2 mutations or ALK-rearrangement.
RESULTS: We diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51-87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1-positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5' telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2-mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma.
CONCLUSION: Our results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced "triple negative" lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series.

Matsuzawa A, Kanno S, Nakayama M, et al.
The BRCA1/BARD1-interacting protein OLA1 functions in centrosome regulation.
Mol Cell. 2014; 53(1):101-14 [PubMed] Related Publications
The breast and ovarian cancer-specific tumor suppressor BRCA1, along with its heterodimer partner BRCA1-associated RING domain protein (BARD1), plays important roles in DNA repair, centrosome regulation, and transcription. To explore further functions of BRCA1/BARD1, we performed mass spectrometry analysis and identified Obg-like ATPase 1 (OLA1) as a protein that interacts with the carboxy-terminal region of BARD1. OLA1 directly bound to the amino-terminal region of BRCA1 and γ-tubulin. OLA1 localized to centrosomes in interphase and to the spindle pole in mitotic phase, and its knockdown resulted in centrosome amplification and the activation of microtubule aster formation. OLA1 with a mutation observed in breast cancer cell line, E168Q, failed to bind BRCA1 and rescue the OLA1 knockdown-induced centrosome amplification. BRCA1 variant I42V also abrogated the binding of BRCA1 to OLA1. These findings suggest that OLA1 plays an important role in centrosome regulation together with BRCA1.

Hes FJ, Ruano D, Nieuwenhuis M, et al.
Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis.
J Med Genet. 2014; 51(1):55-60 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas.
METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs).
RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC.
CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.

Le Gallo M, Bell DW
The emerging genomic landscape of endometrial cancer.
Clin Chem. 2014; 60(1):98-110 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Endometrial cancer is responsible for approximately 74 000 deaths annually among women worldwide. It is a heterogeneous disease comprising multiple histologic subtypes. In the US, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors.
CONTENT: We review the current state of knowledge regarding somatic genomic alterations that occur in serous and endometrioid endometrial tumors. We present this knowledge in a historical context by reviewing the genomic alterations that studies of individual genes and proteins have identified over the past 2 decades or so. We then review very recent comprehensive and systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas.
SUMMARY: The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has produced the first comprehensive molecular classification of these tumors, which has distinguished 4 molecular subgroups: a POLE [polymerase (DNA directed), ε, catalytic subunit] ultramutated subgroup, a hypermutated/microsatellite-unstable subgroup, a copy number-low/microsatellite-stable subgroup, and a copy number-high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors.

Gaujoux S, Salenave S, Ronot M, et al.
Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome.
J Clin Endocrinol Metab. 2014; 99(1):E97-101 [PubMed] Related Publications
BACKGROUND: McCune-Albright syndrome (MAS), which includes polycystic fibrous dysplasia, precocious puberty, and café au lait spots, is a rare disorder caused by somatic activating mutations of the GNAS gene. GNAS mutations have also been implicated in various sporadic tumors, including hepatobiliary and pancreatic neoplasms.
AIM: The aim of this study was to assess the prevalence of hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome.
PATIENTS AND METHODS: Nineteen patients diagnosed between 1995 and 2012 with MAS in a tertiary referral center for rare growth disorders were screened with dedicated gadolinium-enhanced magnetic resonance imaging for hepatobiliary and pancreatic neoplasms between June 2011 and December 2012.
RESULTS: Six (32%) of the 19 screened patients were found to have hepatic, pancreatic, or biliary lesions, excluding liver hemangiomas, liver cysts, and focal nodular hyperplasia. This includes pancreatic ductal lesions observed in 4 patients, including numerous branch-duct intraductal papillary mucinous neoplasms in 3 patients. Biliary lesions were observed in 1 patient, with a large choledochal cyst also involving the left biliary branch. Finally, multiple inflammatory/telangiectatic hepatic adenomas were observed in 2 patients, including 1 with proven somatic GNAS mutation.
CONCLUSION: We describe the first observation of syndromic intraductal papillary mucinous neoplasms and the new association between MAS and pancreatic neoplasms, namely intraductal papillary mucinous neoplasms of the pancreas but also rare hepatobiliary neoplasms including liver adenomas and choledochal cysts. These findings strongly suggest that somatic activating GNAS mutations, possibly through cAMP pathway disorders, are involved in the tumorigenesis of hepatobiliary and pancreatic tissues originating from the foregut endoderm and have led us to use a routine screening by dedicated magnetic resonance imaging including both pancreatobiliary and liver sequences in patients with MAS.

Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al.
Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.
J Clin Oncol. 2013; 31(34):4333-42 [PubMed] Related Publications
PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

De Saedeleer CJ, Porporato PE, Copetti T, et al.
Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration.
Oncogene. 2014; 33(31):4060-8 [PubMed] Related Publications
The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.

Yan ZX, Wu LL, Xue K, et al.
MicroRNA187 overexpression is related to tumor progression and determines sensitivity to bortezomib in peripheral T-cell lymphoma.
Leukemia. 2014; 28(4):880-7 [PubMed] Related Publications
MicroRNAs (miRs) are involved in tumorigenesis by regulating tumor suppressor genes and/or oncogenes. MiR187 was overexpressed in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and associated with high Ki67 expression, elevated lactate dehydrogenase, advanced International Prognostic Index and poor prognosis of patients. In vitro, ectopic expression of miR187 in T-lymphoma cell lines accelerated tumor cell proliferation, whereas treatment with miR187 inhibitor reduced cell growth. MiR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERK) and AKT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib. Bortezomib inhibited T-lymphoma cell proliferation by downregulating miR187, dephosphorylating ERK and AKT and degrading MYC. In a murine xenograft model established with subcutaneous injection of Jurkat cells, bortezomib particularly retarded the growth of miR187-overexpressing tumors, consistent with the downregulation of miR187, Ki67 and MYC expression. Collectively, these findings indicated that miR187 was related to tumor progression in PTCL-NOS through modulating Ras-mediated ERK/AKT/MYC axis. Although potentially oncogenic, miR187 indicated the sensitivity of T-lymphoma cells to bortezomib. Cooperatively targeting ERK and AKT could be a promising clinical strategy in treating MYC-driven lymphoid malignancies.

Agbor AA, Göksenin AY, LeCompte KG, et al.
Human Pol ε-dependent replication errors and the influence of mismatch repair on their correction.
DNA Repair (Amst). 2013; 12(11):954-63 [PubMed] Related Publications
Mutations in human DNA polymerase (Pol) ε, one of three eukaryotic Pols required for DNA replication, have recently been found associated with an ultramutator phenotype in tumors from somatic colorectal and endometrial cancers and in a familial colorectal cancer. Possibly, Pol ε mutations reduce the accuracy of DNA synthesis, thereby increasing the mutational burden and contributing to tumor development. To test this possibility in vivo, we characterized an active site mutant allele of human Pol ε that exhibits a strong mutator phenotype in vitro when the proofreading exonuclease activity of the enzyme is inactive. This mutant has a strong bias toward mispairs opposite template pyrimidine bases, particularly T • dTTP mispairs. Expression of mutant Pol ε in human cells lacking functional mismatch repair caused an increase in mutation rate primarily due to T • dTTP mispairs. Functional mismatch repair eliminated the increased mutagenesis. The results indicate that the mutant Pol ε causes replication errors in vivo, and is at least partially dominant over the endogenous, wild type Pol ε. Since tumors from familial and somatic colorectal patients arise with Pol ε mutations in a single allele, are microsatellite stable and have a large increase in base pair substitutions, our data are consistent with a Pol ε mutation requiring additional factors to promote tumor development.

Luyckx V, Durant JF, Camboni A, et al.
Is transplantation of cryopreserved ovarian tissue from patients with advanced-stage breast cancer safe? A pilot study.
J Assist Reprod Genet. 2013; 30(10):1289-99 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PURPOSE: To assess the safety of reimplantation of cryopreserved ovarian tissue from advanced-stage breast cancer patients.
METHODS: Cryopreserved ovarian cortical fragments were obtained from 13 advanced-stage breast cancer patients aged 17-35 years. After thawing, part of the ovarian cortical tissue was grafted to severe combined immunodeficient mice for 6 months. The presence of malignant mammary cells in ovarian tissue was evaluated after thawing as well as after grafting by 1) histology and immunohistochemistry (epithelial membrane antigen, Her2/neu and gross cystic disease fluid protein 15 identification), and 2) detection of the MGB2 gene by qPCR.
RESULTS: No malignant cells were evidenced by histology and immunohistochemistry. None of the mice died during the 6-month grafting period, nor developed macroscopically visible masses. MGB2 gene expression was detected by qPCR and confirmed by sequencing in frozen-thawed ovarian tissue in 4 cases and in grafts in 1 case.
CONCLUSIONS: This pilot study is the first to evaluate the risk of contamination of cryopreserved ovarian tissue from advanced-stage breast cancer patients by xenotransplantation for 6 months to immunodeficient mice, associated with more conventional screening methods. Our xenografting results are reassuring, but caution needs to be exercised, as MGB2 gene expression was detected in some cases. Larger numbers of ovarian tissue samples from patients with advanced-stage breast cancer are required to confirm our findings before ovarian tissue transplantation can be contemplated in these patients.

Stepanenko AA, Vassetzky YS, Kavsan VM
Antagonistic functional duality of cancer genes.
Gene. 2013; 529(2):199-207 [PubMed] Related Publications
Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and "paradoxical" effects of different anticancer drugs depending on the cellular genetic context/signaling network are discussed.

Mollet L, Robinet P, Dubois M, et al.
Opposing Mcl-1, the GALIG proapoptotic gene is upregulated as neutrophils die and underexpressed in Acute Myeloid Leukemia cells.
Mol Immunol. 2013; 56(1-2):123-8 [PubMed] Related Publications
GALIG gene expression induces apoptosis in cultured cells through a pathway still under investigation. It is highly expressed in leukocytes but weakly detectable in bone marrow, suggesting a role in the myeloid lineage homeostasis. We show here that GALIG-induced cell death is counteracted by the overexpression of MCL-1, a pro-survival member of the Bcl2 family. Moreover, during spontaneous neutrophil apoptosis, a substantial increase in GALIG gene expression is observed: GALIG still opposes MCL-1. Finally, in bone marrow and peripheral blood cells from patients with Acute Myeloid Leukemia type 2, the level of GALIG transcripts is massively down-regulated when compared to their normal counterparts, while MCL-1 is expressed to the same extent. These data suggest that GALIG could be a key player in the cell death pathway involved in leukocytes homeostasis and myeloid malignancies.

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