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AFDN
Gene Summary
Gene: AFDN; afadin, adherens junction formation factor
Aliases: AF6, MLLT4, MLL-AF6, l-afadin
Location: 6q27
Summary: This gene encodes a multi-domain protein involved in signaling and organization of cell junctions during embryogenesis. It has also been identified as the fusion partner of acute lymphoblastic leukemia (ALL-1) gene, involved in acute myeloid leukemias with t(6;11)(q27;q23) translocation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, however, not all have been fully characterized.[provided by RefSeq, May 2011]
Databases: OMIM, HGNC, Ensembl, GeneCard, Gene
Protein: afadin
Source: NCBIAccessed: 31 August, 2019
What does this gene/protein do?
AFDN is implicated in:
- adherens junction organization
- apical part of cell
- cell adhesion
- cell adhesion molecule binding
- cell junction
- cell junction assembly
- cell-cell adherens junction
- cell-cell junction
- cell-cell junction organization
- cell-cell signaling
- cytoplasm
- cytosol
- nucleolus
- nucleus
- plasma membrane
- protein C-terminus binding
- signal transduction
Data from Gene Ontology via CGAP [Hide]
Pathways: What pathways are this gene/protein implicaed in?
AFDN is involved in:
- Adherens junction KEGG
- Leukocyte transendothelial migration KEGG
- Tight junction KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP [Hide]
Specific Cancers (1)
Graph generated 01 September 2019 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.
MLLT4
DNA Sequence Analysis
Sequence Tagged Sites
Proto-Oncogenes
Myeloid Leukemia
Myosins
KMT2A
ras Proteins
MAP Kinase Signaling System
Microfilament Proteins
Tight Junctions
Sequence Deletion
Oncogene Fusion Proteins
Cloning, Molecular
Xenograft Models
Translocation
Tumor Suppressor Gene
Acute Myeloid Leukaemia
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Entity Topic PubMed Papers
Acute Myeloid Leukaemia (AML) t(6;11)(q27;q23) in Acute Myeloid Leukemia
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: AFDN (cancer-related)
Yang H, Jin L, Sun X
A thirteen‑gene set efficiently predicts the prognosis of glioblastoma.
Mol Med Rep. 2019; 19(3):1613-1621 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most common type of brain cancer; it usually recurs and patients have a short survival time. The present study aimed to construct a gene expression classifier and to screen key genes associated with GBM prognosis. GSE7696 microarray data set included samples from 10 recurrent GBM tissues, 70 primary GBM tissues and 4 normal brain tissues. Seed genes were identified by the 'survival' package in R and subjected to pathway enrichment analysis. Prognostic genes were selected from the seed genes using the 'rbsurv' package in R, unsupervised hierarchical clustering, survival analysis and enrichment analysis. Multivariate survival analysis was performed for the prognostic genes, and the GBM data set from The Cancer Genome Atlas database was utilized to validate the prognostic genes. Of the 1,785 seed genes analyzed, 13 prognostic feature genes, including collagen type XXVIII α1 chain (COL28A1), PDS5 cohesin‑associated factor A (PDS5A), zinc‑finger DHHC‑type containing 2 (ZDHHC2), zinc‑finger protein 24 (ZNF24), myosin VA (MYO5A) and myeloid/lymphoid or mixed‑lineage leukemia translocated to 4 (MLLT4), were identified. These genes performed well on sample classification and prognostic risk differentiation, and six pathways, including adherens junction, cyclic adenosine 3',5'‑monophosphate signaling and Ras signaling pathways, were enriched for these feature genes. The high‑risk group was slightly older compared with the low‑risk group. The validation data set confirmed the prognostic value of the 13 feature genes for GBM; of these, COL28A1, PDS5A, ZDHHC2, ZNF24, MYO5A and MLLT4 may be crucial. These results may aid the understanding of the pathogenesis of GBM and provide important clues for the development of novel diagnostic markers or therapeutic targets.
Peterson JF, Baughn LB, Pearce KE, et al.
KMT2A (MLL) rearrangements observed in pediatric/young adult T-lymphoblastic leukemia/lymphoma: A 10-year review from a single cytogenetic laboratory.
Genes Chromosomes Cancer. 2018; 57(11):541-546 [PubMed] Related Publications
T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T-ALL/LBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3'KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T-ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.
Related: FISH
Chen X, Wang F, Zhang Y, et al.
Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia.
Leuk Res. 2018; 72:99-104 [PubMed] Related Publications
Fusion genes are major molecular biological abnormalities in hematological malignancies. To depict the common recurrent gene-fusion landscape in acute lymphoblastic leukemia (ALL), 36 recurrent fusion genes in hematologic malignancies were assessed using multiplex-nested RT-PCR in 2479 patients with de novo ALL. 17 kinds of distinct fusion genes were detected in 712 (28.72%) cases. Co-occurrence of different fusion genes was observed in 6 (0.24%) patients. Incidence of fusion genes in B-ALL was significantly higher than in T-ALL (31.40% vs. 14.50%, P < 0.001). Pediatric ALL had higher prevalence of ETV6-RUNX1, TCF3-PBX1, and STIL-TAL1, while BCR-ABL1 and SET-NUP214 were more common in adult ALL. BCR-ABL1, TCF3-PBX1, KMT2A-AFF1 and ETV6-RUNX1 were more frequent in B-ALL. On the contrary, KMT2A-MLLT4, SET-NUP214 and STIL-TAL1 were of higher incidence in T-ALL. In comparison with Western cohorts, the incidence of BCR-ABL1 (5.94%) was much higher in our series, while the occurrence of ETV6-RUNX1 (13.19%) was significantly lower in pediatric B-ALL patients in our study than in Western reports. This study provides a genetic landscape of common fusion genes in ALL patients and may serve as a foundation for further improvement of a fusion gene screening panel for clinical applications.
Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology
Numata A, Kwok HS, Kawasaki A, et al.
The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.
Nat Commun. 2018; 9(1):1622 [PubMed] Free Access to Full Article Related Publications
Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
Related: Acute Myeloid Leukemia (AML)
Iijima-Yamashita Y, Matsuo H, Yamada M, et al.
Multiplex fusion gene testing in pediatric acute myeloid leukemia.
Pediatr Int. 2018; 60(1):47-51 [PubMed] Related Publications
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required.
METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: AML1(RUNX1)-ETO(RUNX1T1), CBFB-MYH11, MLL(KMT2A)-AF9(MLLT3), MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA.
RESULTS: Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH.
CONCLUSIONS: Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML.
Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology
Matsuo H, Iijima-Yamashita Y, Yamada M, et al.
Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia.
BACKGROUND: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points.
METHODS: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30-40 days apart following diagnosis.
RESULTS: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients.
CONCLUSIONS: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.
Smith MJ, Ottoni E, Ishiyama N, et al.
Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.
Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.
Related: Leukemia
Yang H, Cao T, Gao L, et al.
The incidence and distribution characteristics of MLL rearrangements in Chinese acute myeloid leukemia patients by multiplex nested RT-PCR.
Technol Health Care. 2017; 25(S1):259-265 [PubMed] Related Publications
Occurrence of MLL (Mixed Lineage Leukemia) gene rearrangements indicates poor prognosis in acute myeloid leukemia (AML) patients. This is the first study to report the positive rate and distribution characteristics of MLL rearrangements in AML patients in north China. We used multiplex nested real time PCR (RT-PCR) to screen for incidence of 11 MLL rearrangements in 433 AML patients. Eleven MLL rearrangements included (MLL-PTD, MLL-AF9, MLL-ELL, MLL-AF10, MLL-AF17, MLL-AF6, MLL-ENL, MLL-AF1Q, MLL-CBP, MLL-AF1P, MLL-AFX1). There were 68 AML patients with MLL rearrangements, and the positive rate was 15.7%. MLL-PTD (4.84%) was detected in 21 patients, MLL-AF9 in 15, (3.46%), MLL-ELL in 10 (2.31%), MLL-AF10 in 8 (1.85%), MLL-AF1Q in 2 (0.46%), 3 cases each of MLL-AF17, MLL-AF6, MLL-ENL (0.69% each), a and single case each of MLL-CBP, MLL-AF1P, and MLL-AFX1 (0.23% each). The highest rate of MLL rearrangements was found in 24 patients with M5 subtype AML, occurring in 24 cases (35.3%). MLL rearrangements occurred in 21 patients with M2 subtype AML (30.9%), and in 10 patients with M4 subtype AML (14.7%). Screening fusion genes by multiplex nested RT-PCR is a convenient, fast, economical, and accurate method for diagnosis and predicting prognosis of AML.
Xu X, Nagel S, Quentmeier H, et al.
KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia.
Leuk Lymphoma. 2018; 59(1):204-213 [PubMed] Related Publications
KDM3B reportedly shows both tumor-suppressive and tumor-promoting activities in leukemia. The function of KDM3B is likely cell-type dependent and its seeming functional discordance may reflect its phenotypic dependence on downstream targets. Here, we first showed the underexpression of KDM3B in acute myeloid leukemia (AML) patients and AML cell lines with MLL-AF6/9 or PML-RARA translocations. Overexpression of KDM3B repressed colony formation of AML cell line with 5q deletion. We then performed global microarray profiling to identify potential downstream targets of KDM3B, notably HOXA1, which was verified by real time PCR and Western blotting. We further showed KDM3B binding at retinoic acid response elements (RARE) but not at the promoter region of HOXA1 gene. KDM3B knockdown resulted in increased mono-methylation but decreased di-methylation of H3K9 at RARE while eschewing the promoter region of HOXA1. Collectively, we found that KDM3B exhibits potential tumor-suppressive activity and transcriptionally modulates HOXA1 expression via RARE in AML.
Feng L, Houck JR, Lohavanichbutr P, Chen C
Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa.
Oncotarget. 2017; 8(19):31521-31531 [PubMed] Free Access to Full Article Related Publications
Oral cavity and oropharyngeal squamous cell carcinoma (OSCC) is a major cancer type in the head and neck region. To better understand the roles long non-coding RNA (lncRNA) play in OSCC carcinogenesis, we compared the expression levels of 3,054 probe sets for lncRNAs between 167 OSCCs and 45 healthy oral mucosa using an Affymetrix HG U133 plus 2.0 array dataset. We found 658 lncRNA transcripts (790 probe sets) to be significantly differentially expressed using a criteria of FDR < 0.01, with 36 of them (39 probe sets) showing more than a 2-fold change. We further validated the top differentially expressed lncRNAs in three independent datasets from Gene Expression Omnibus (GEO) repository: GSE42743, GSE9844, and GSE6791. Fourteen lncRNAs (15 probe sets) were validated in all three datasets using the criteria FDR < 0.01: LOC441178, C5orf66-AS1, HCG22, FLG-AS1, CCL14/CCL15-CCL14, LOC100506990, TRIP10, PCBP1-AS1, LINC01315, LINC00478, COX10-AS1/LOC100506974, MLLT4-AS1, MIR31HG, and DUXAP10/LINC01296. Three lncRNAs in the validated list which showed the highest fold change (LOC441178, HCG22 and C5orf66-AS1) were verified by quantitative RT-PCR in a subset of 20 OSCCs and 10 control samples. In silico prediction of their functional role has given us directions for further investigation.
Related: Oral Cancer
Milani G, Lana T, Bresolin S, et al.
Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways.
Mol Cancer Res. 2017; 15(6):683-695 [PubMed] Related Publications
Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemia
Related: Leukemia Signal Transduction
Pichler M, Stiegelbauer V, Vychytilova-Faltejskova P, et al.
Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.
Clin Cancer Res. 2017; 23(5):1323-1333 [PubMed] Free Access to Full Article Related Publications
Related: Colorectal (Bowel) Cancer MicroRNAs
Ney Garcia DR, de Souza MT, de Figueiredo AF, et al.
Molecular characterization of KMT2A fusion partner genes in 13 cases of pediatric leukemia with complex or cryptic karyotypes.
Hematol Oncol. 2017; 35(4):760-768 [PubMed] Related Publications
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1 in one patient each. Reciprocal reading by long-distance inverse PCR also disclosed KMT2A fusions with PITPNA in one patient, with LOC100132273 in another patient, and with DNA sequences not compatible with any gene in three patients. The most common KMT2A breakpoint region was intron/exon 9 (3/8 patients), followed by intron/exon 11 and 10. Finally, multicolor banding revealed breakpoints in other chromosomes whose biological and prognostic implications remain to be determined. We conclude that the combination of molecular techniques used in this study can efficiently identify KMT2A fusion partners in complex pediatric acute leukemia karyotypes. Copyright © 2016 John Wiley & Sons, Ltd.
Related: Cancer Cytogenetics Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology
Micci F, Gorunova L, Agostini A, et al.
Cytogenetic and molecular profile of endometrial stromal sarcoma.
Genes Chromosomes Cancer. 2016; 55(11):834-46 [PubMed] Free Access to Full Article Related Publications
Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. © 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.
Related: Cancer Cytogenetics FISH
Xu Y, Chang R, Peng Z, et al.
Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression.
Nat Commun. 2015; 6:7184 [PubMed] Related Publications
Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.
Related: Cancer of the Pancreas Pancreatic Cancer
Yamamoto T, Mori T, Sawada M, et al.
Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.
BMC Cancer. 2015; 15:275 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: AF-6/afadin plays an important role in the formation of adherence junctions. In breast and colon cancer, loss of AF-6/afadin induces cell migration and cell invasion. We aimed to elucidate the role of AF-6/afadin in human endometrial cancer.
METHODS: Morphology and AF-6/afadin expression in endometrial cancer cell lines was investigated by 3-dimensional culture. We used Matrigel invasion assay to demonstrate AF-6/afadin knockdown induced invasive capability. Cell proliferation assay was performed to estimate chemoresistance to doxorubicin, paclitaxel and cisplatin induced by AF-6/afadin knockdown. The associations between AF-6/afadin expression and clinicopathological status were determined by immunohistochemical analysis in endometrial cancer tissues. Informed consent was obtained from all patients before the study.
RESULTS: The majority of cell clumps in 3-dimensional cultures of Ishikawa cells that strongly expressed AF-6/afadin showed round gland-like structures. In contrast, the cell clumps in 3-dimensional cultures of HEC1A and AN3CA cells-both weakly expressing AF-6/afadin-showed irregular gland-like structures and disorganized colonies with no gland-like structures, respectively. AF-6/afadin knockdown resulted in reduced number of gland-like structures in 3-dimensional cultures and enhancement of cell invasion and phosphorylation of ERK1/2 and Src in the highly AF-6/afadin-expressing endometrial cancer cell line. Inhibitors of MAPK/ERK kinase (MEK) (U0126) and Src (SU6656) suppressed the AF-6/afadin knockdown-induced invasive capability. AF-6/afadin knockdown induced chemoresistance to doxorubicin, paclitaxel and cisplatin in Ishikawa cells, not in HEC1A. Immunohistochemical analysis showed that AF-6/afadin expression was significantly associated with myometrial invasion and high histological grade.
CONCLUSIONS: AF-6/afadin regulates cell morphology and invasiveness. Invasive capability is partly regulated through the ERK and Src pathway. The inhibitors to these pathways might be molecular-targeted drugs which suppress myometrial invasion in endometrial cancer. AF-6/afadin could be a useful selection marker for fertility-sparing therapy for patients with atypical hyperplasia or grade 1 endometrioid adenocarcinoma with no myometrial invasion. AF-6/afadin knockdown induced chemoresistance especially to cisplatin. Therefore, loss of AF-6/afadin might be a predictive marker of chemoresistance to cisplatin.
Related: Cisplatin Endometrial (Uterus) Cancer Endometrial Cancer Paclitaxel
Deshpande AJ, Deshpande A, Sinha AU, et al.
AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.
Cancer Cell. 2014; 26(6):896-908 [PubMed] Free Access to Full Article Related Publications
Homeotic (HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at HOX loci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1-to-H3K79me2 conversion is regulated by the DOT1L cofactor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6, and NUP98-NSD1 fusions-mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1-transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/AF10 complex may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.
Related: Acute Myeloid Leukemia (AML) NUP98
Di Narzo AF, Tejpar S, Rossi S, et al.
Test of four colon cancer risk-scores in formalin fixed paraffin embedded microarray gene expression data.
J Natl Cancer Inst. 2014; 106(10) [PubMed] Related Publications
BACKGROUND: Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification.
METHODS: Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase.
RESULTS: All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score.
CONCLUSIONS: The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different.
Manara E, Baron E, Tregnago C, et al.
MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia.
Blood. 2014; 124(2):263-72 [PubMed] Related Publications
A rare location, t(6;11)(q27;q23) (MLL-AF6), is associated with poor outcome in childhood acute myeloid leukemia (AML). The described mechanism by which MLL-AF6, through constitutive self-association and in cooperation with DOT-1L, activates aberrant gene expression does not explain the biological differences existing between t(6;11)-rearranged and other MLL-positive patients nor their different clinical outcome. Here, we show that AF6 is expressed in the cytoplasm of healthy bone marrow cells and controls rat sarcoma viral oncogene (RAS)-guanosine triphosphate (GTP) levels. By contrast, in MLL-AF6-rearranged cells, AF6 is found localized in the nucleus, leading to aberrant activation of RAS and of its downstream targets. Silencing MLL-AF6, we restored AF6 localization in the cytoplasm, thus mediating significant reduction of RAS-GTP levels and of cell clonogenic potential. The rescue of RAS-GTP levels after MLL-AF6 and AF6 co-silencing confirmed that MLL-AF6 oncoprotein potentiates the activity of the RAS pathway through retention of AF6 within the nucleus. Exposure of MLL-AF6-rearranged AML blasts to tipifarnib, a RAS inhibitor, leads to cell autophagy and apoptosis, thus supporting RAS targeting as a novel potential therapeutic strategy in patients carrying t(6;11). Altogether, these data point to a novel role of the MLL-AF6 chimera and show that its gene partner, AF6, is crucial in AML development.
Related: Chromosome 11 Chromosome 6
Lim JH, Jang S, Park CJ, et al.
FISH analysis of MLL gene rearrangements: detection of the concurrent loss or gain of the 3' signal and its prognostic significance.
Int J Lab Hematol. 2014; 36(5):571-9 [PubMed] Related Publications
INTRODUCTION: The rearrangement of the mixed-lineage leukemia (MLL) gene occurs through translocations and insertions involving a variety of partner chromosome genes. However, there are few studies on aberrant MLL signal patterns such as concurrent 3' MLL deletion.
METHODS: A total of 84 patients with acute leukemia (AL) who had MLL rearrangements detected by florescence in situ hybridization (FISH) were enrolled in the study. The distribution of MLL fusion partner genes was analyzed, and aberrant MLL signals were evaluated.
RESULTS: Seventy-seven (91.7%) patients had MLL rearrangements, involving previously described translocation partner genes (TPGs). Among these TPGs, the frequencies of MLLT3, AFF1, MLLT4, and ELL were 29.8%, 17.9%, 15.5%, and 13.1%, respectively. A high frequency of MLLT4 in our study was due to the high proportion of acute myeloid leukemia cases in pediatric and adult patients. Aberrant MLL signals were found in 18 patients: 11 (61.1%) with 3' MLL signal loss and 7 with 3' MLL signal gain. All cases with 3' MLL signal gain were due to an extra derivative partner chromosome. The median overall survival period of patients with 3' MLL gain was shorter than that in patients without aberrant MLL signal patterns.
CONCLUSION: Aberrant MLL signals were frequently detected by FISH analysis. The 3' MLL gain was associated with poor prognosis in patients with AL. Therefore, it is important to detect aberrant MLL signal patterns using FISH analysis.
Related: FISH Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology
Shiba N, Ichikawa H, Taki T, et al.
NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.
Genes Chromosomes Cancer. 2013; 52(7):683-93 [PubMed] Related Publications
The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
Related: Chromosome 11 Chromosome 5 Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology
Meyer C, Hofmann J, Burmeister T, et al.
The MLL recombinome of acute leukemias in 2013.
Leukemia. 2013; 27(11):2165-76 [PubMed] Free Access to Full Article Related Publications
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
Related: Leukemia Childhood Leukaemia Leukemia - Molecular Biology
Wang C, Cai X, Chen B, et al.
Up-regulation of tissue inhibitor of metalloproteinase-2 promotes SHI-1 cell invasion in nude mice.
Leuk Lymphoma. 2013; 54(12):2707-11 [PubMed] Related Publications
The role of tissue inhibitor of metalloproteinase-2 (TIMP-2) in extramedullary infiltration of acute leukemia is unclear. We demonstrated in our previous study that the up-regulation of TIMP-2 promoted SHI-1 cell invasion in vitro. We investigated in the present study whether TIMP-2 would have the same effect in vivo. A retroviral vector carrying human TIMP-2 cDNA was constructed and transfected into SHI-1 cells. Three subclone cells (S1, S2 and S3) that highly expressed TIMP-2 were selected to establish nude mouse models of acute leukemia. Times of leukemic onset in mice of S1, S2 and S3 groups were all earlier than that of the SHI-1 group, whereas the survival times of S1, S2 and S3 groups were all shorter than that of the SHI-1 group (p < 0.05). Histopathological results demonstrated severe leukemic infiltration in numerous organs in each group. Reverse transcription polymerase chain reaction (RT-PCR) assay showed that several organs expressed the MLL/F6 fusion gene. Moreover, the numbers of organs infiltrated by leukemic cells in S1, S2 and S3 groups were more than those in the SHI-1 group (p < 0.05). Up-regulating TIMP-2 expression enhanced SHI-1 cell invasion in nude mice and resulted in more severe leukemia infiltration. This phenomenon suggests that targeted therapy with TIMP-2 for acute leukemia should be performed with prudence.
Related: Cancer Prevention and Risk Reduction TIMP2
Türkmen S, Timmermann B, Bartels G, et al.
Involvement of the MLL gene in adult T-lymphoblastic leukemia.
Genes Chromosomes Cancer. 2012; 51(12):1114-24 [PubMed] Related Publications
While the MLL "recombinome" is relatively well characterized in B-cell precursor acute lymphoblastic leukemia (BCP ALL), available data for adult acute T-lymphoblastic leukemia (T-ALL) are scarce. We performed fluorescence in situ hybridization (FISH) for an MLL split signal on 223 adult T-ALL samples obtained within the framework of the German Multicenter ALL 07/2003 therapy trial. Three biphenotypic leukemias (T-ALL/AML) were also included in the analysis. Samples showing any alteration by FISH were further investigated to characterize the MLL aberration. In addition, they were investigated for common genetic lesions known in T-ALL. Twenty-two cases (9.5%) showed an abnormal MLL signal by FISH analysis. Most of these appeared to be deletions or gains but in five cases (2.1%) a chromosomal translocation involving the MLL gene was identified. The translocation partners and chromosomal breakpoints were molecularly characterized. Three T-ALLs had an MLL-AF6/t(6;11) and two biphenotypic leukemias had an MLL-ELL/t(11;19). The chromosomal breakpoints in two of the MLL-AF6-positive cases were located outside the classical MLL major breakpoint cluster known from BCP ALL. In conclusion, the spectrum of MLL translocation partners in adult T-ALL much more resembles that of AML than that of BCP ALL and thus the mechanisms by which MLL contributes to leukemogenesis in adult T-ALL appear to differ from those in BCP ALL. Proposals are made for the diagnostic assessment of MLL fusion genes in adult T-ALL.
Related: FISH Acute Lymphocytic Leukemia (ALL)
Cerveira N, Lisboa S, Correia C, et al.
Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution.
Mol Oncol. 2012; 6(5):553-64 [PubMed] Free Access to Full Article Related Publications
Chromosomal rearrangements affecting the MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant.
Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology MLLT1 MLLT2
Bindels EM, Havermans M, Lugthart S, et al.
EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs.
Blood. 2012; 119(24):5838-49 [PubMed] Free Access to Full Article Related Publications
The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs.
Related: Chromosome 11 Acute Myeloid Leukemia (AML) EVI1
Fournier G, Cabaud O, Josselin E, et al.
Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth.
Oncogene. 2011; 30(36):3862-74 [PubMed] Related Publications
Afadin/AF6, an F-actin-binding protein, is ubiquitously expressed in epithelia and has a key role during development, through its regulatory role in cell-cell junction organization. Afadin loss of expression in 15% of breast carcinoma is associated with adverse prognosis and increased risk of metastatic relapse. To determine the role of afadin in breast cancer, we studied the functional consequences of afadin protein extinction using in vitro and in vivo models. Three different breast cancer cell lines representative of the major molecular subtypes were stably repressed for afadin expression (knockdown of afadin (afadin KD)) using RNA interference. Collective and individual migrations as well as Matrigel invasion were markedly increased in afadin KD cells. Heregulin-β1 (HRG-β1)-induced migration and invasion were increased by twofold in afadin KD cells. Conversely, ectopic expression of afadin in the afadin-negative T47D cell line inhibited spontaneous and HRG-β1-induced migrations. RAS/MAPK and SRC kinase pathways were activated in afadin KD cells. Activation levels positively correlated with migration and invasion strength. Use of MEK1/2 (U0126) and SRC kinases (SU6656) inhibitors reduced afadin-dependent migration and invasion. Afadin extinction in the SK-BR-3 cell line markedly accelerated tumor growth development in mouse mammary gland and lung metastasis formation. These results may explain why the loss of afadin expression in tumors correlates with high tumor size and poor metastasis-free survival in patients.
Related: Breast Cancer
Liedtke M, Ayton PM, Somervaille TC, et al.
Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6.
Blood. 2010; 116(1):63-70 [PubMed] Free Access to Full Article Related Publications
MLL is a common target for chromosomal translocations associated with acute leukemia resulting in its fusion with a large variety of nuclear or cytoplasmic proteins that may activate its oncogenic properties by distinct but poorly understood mechanisms. The MLL-AF6 fusion gene represents the most common leukemogenic fusion of mixed lineage leukemia (MLL) to a cytoplasmic partner protein. Here, we identified a highly conserved Ras association (RA1) domain at the amino-terminus of AF6 as the minimal region sufficient for MLL-AF6 mediated myeloid progenitor immortalization in vitro and short latency leukemogenesis in vivo. Moreover, the ability of RA1 to activate MLL oncogenesis is conserved with its Drosophila ortholog, Canoe. Although the AF6 RA1 domain has previously been defined as an interaction surface for guanosine triphosphate-bound Ras, single amino acid substitutions known to abolish the AF6-Ras interaction did not abrogate MLL-AF6-mediated oncogenesis. Furthermore, fusion of MLL to heterologous RA domains of c-Raf1 or RalGDS, or direct fusion of MLL to constitutively active K-RAS, H-RAS, or RAP1 was not sufficient for oncogenic activation of MLL. Rather, the AF6 RA1 domain efficiently mediated self-association, suggesting that constitutive MLL self-association is a more common pathogenic mechanism for MLL oncogenesis than indicated by previous studies of rare MLL fusion partners.
Banga SS, Peng L, Dasgupta T, et al.
PHF10 is required for cell proliferation in normal and SV40-immortalized human fibroblast cells.
Cytogenet Genome Res. 2009; 126(3):227-42 [PubMed] Free Access to Full Article Related Publications
Normal human diploid fibroblasts have limited life span in culture and undergo replicative senescence after 50-60 population doublings. On the contrary, cancer cells typically divide indefinitely and are immortal. Expression of SV40 large T and small t antigens in human fibroblasts transiently extends their life span by 20-30 population doublings and facilitates immortalization. We have identified a rearrangement in chromosome 6 shared by SV40-transformed human fibroblasts. Rearrangements involving chromosome 6 are among the most frequent in human carcinogenesis. In this paper, we extend analysis of the 6q26-q27 region, a putative site for a growth suppressor gene designated SEN6 involved in immortalization of SV40-transformed cells. Detailed molecular characterization of the rearranged chromosomes (6q*, normal appearing; and 6q(t), translocated) in the SV40-immortalized cell line HALneo by isolating each of these 2 chromosomes in mouse/HAL somatic cell hybrids is presented. Analysis of these mouse/HAL somatic cell hybrids with polymorphic and nonpolymorphic markers revealed that the 6q* has undergone a chromosomal break in the MLLT4 gene (alias AF6). This result in conjunction with previous published observations leads us to conclude that SEN6 lies between MLLT4 and TBP at chromosomal region 6q27. Examination of different genes (MLLT4, DLL1, FAM120B, PHF10) located within this interval that are expressed in HS74 normal fibroblast cells reveals that overexpression of epitope-tagged truncated PHF10 cDNAs resulted in reduced cell proliferation in multiple cell lines. Paradoxically, down-regulation of PHF10 by RNAi also resulted in loss of cell proliferation in normal fibroblast cells, indicating PHF10 function is required for cell growth. Taken together, these observations suggest that decreased cell proliferation with epitope-tagged truncated PHF10 proteins may be due to dominant negative effects or due to unregulated expression of these mutant proteins. Hence we conclude that PHF10 is not SEN6 but is required for cell growth.
Related: Chromosome 6 FISH
Kobayashi S, Obata M, Hagihara M, et al.
The presence of mature granulocytes/monocytes derived from leukemic cells in MLL-associated leukemia.
Int J Hematol. 2009; 90(5):591-596 [PubMed] Related Publications
We observed the mature granulocytes/monocytes derived from leukemic cells in patients with acute myeloid leukemia who present mixed lineage leukemia gene (MLL). Morphologic observation and fluorescence in situ hybridization analysis (FISH) for chromosome 11q23 abnormality were studied, and a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was done to identify the fusion partners with MLL. The bone marrow cells with FISH signals of MLL showed the cell differentiation of the myeloid and/or monocytic lineages in 4 of 6 AML patients. MLL partner genes were AF6, AF9, ELL, and ENL, respectively. There was no correlation between the fusion partner and the appearance of mature cells derived from MLL clones. RT-PCR showed the fusion between MLL exon 9 or 10 and the partner genes in mature granulocytes/monocytes. These findings suggest that subgroup of leukemia cells with MLL rearrangement has the differentiation potential of leukemic cells and mature granulocytes/monocytes derived from MLL clones may be biologically different from normal mature cells.
Cite this page: Cotterill SJ. MLLT4, Cancer Genetics Web: http://www.cancer-genetics.org/MLLT4.htm Accessed:
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Hundred of first persons from leading development companies will assemble on the most magnificent Moscow stage on June 19th, 2007 to be involved in yearly Building Awards ceremony in the field of development.
Within the bounds of Building Awards 2007 members of advisory committee that will consist of Russian and foreign experts who connected with Russian developers, will determine the best developers in such nominations as office, warehouse, trading, hotel, residential and out-of-town real estate, tall building and town-planning.
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Do Child Outcomes of All Disciplinary Enforcements Vary By Ethnicity?
The association of spanking with externalizing behavior problems varies by ethnicity in many studies comparing Black and White Americans. This study investigates whether the outcomes of other disciplinary enforcements also varies by ethnicity in 7- to 11-year-olds. Ethnic interactions were found for spanking, privilege removal, grounding, and, marginally, for sending children to their room. The significant simple effects were never detrimental for Hispanics or Blacks and never beneficial for Whites. At these ages, privilege removal appeared effective except for Whites and grounding was effective for Hispanics. Spanking and sending children to their room showed opposite effects for Blacks and Whites. This study uses data from two waves (1996 & 1998) of the well-known National Longitudinal Survey of Youth (NLSY). The children were 7.5 to 11.4 years olds in 1996 and included 53% boys. The NLSY oversampled ethnic minorities, yielding 22% Hispanic-Americans (HAs), 27% African-Americans (AAs), and 51% European-Americans (EAs). The sample size was 868 for most analyses after dropping cases with missing data.
Larzelere, Robert E., Ronald B. Jr. Cox, Ketevan Danelia and Jelani Mandara. "Do Child Outcomes of All Disciplinary Enforcements Vary By Ethnicity?." Presented: Little Rock, AR, Annual Conference of the National Council on Family Relations, November 2008.
The purpose of this study was to uncover dispositional types of parents among 4754 adolescents and their parents from the NLSY-79. Cluster analytic methods were used and five qualitatively different parenting types were uncovered. Moreover, the profiles and effects of parenting type were consistent for African, European, and Hispanic Americans. Authoritative and strict authoritative parents had much higher SES, achievement and mental health than the permissive, authoritarian or neglectful parents. Even after adjusting for the background factors, those with authoritative parents had higher achievement, fewer depressive symptoms and less externalizing problems for each ethnic group. However, European American youth were twice as likely as Hispanic and African American youth to have authoritative parents. It was concluded that the traditional conception of authoritative parenting may be optimal for all American ethnic groups, even if it is not culturally normative for some. A stricter version of authoritative parenting was also adequate.
Mandara, Jelani. "An Empirically Derived Parenting Typology." Working Paper, Program in Human Development and Social Policy, Northwestern University, 2010.
Presentation: Montreal QC, Canada: Invited Address, SRCD Biennial Meeting, March 31 - April 2, 2011.
In this talk, Jelani Mandara will argue that ethnic differences in achievement are completely social in origin. He will argue that the significant differences in SES of past generations led to ethnic differences in the use of achievement oriented parenting strategies. Such parenting strategies are fundamental to the development of certain cognitive skills and achievement motivation, which, along with school factors, account for current ethnic disparities in achievement. Using SEM with latent variables to test the tenets of this model with data from the NLSY79, NLSY97 and smaller datasets, Dr. Mandara will show that once SES and parenting are appropriately measured, the family factors explain no less than 90% of the achievement gap in each dataset. He also will show that these achievement disparities are somewhat different by gender, birth order, and region of the country. Dr. Mandara will conclude by discussing the importance of effective parent training interventions and other policy recommendations.
Mandara, Jelani. "Economic Resources and Achievement Oriented Parenting Explain Most Ethnic Disparities in Child and Adolescent Achievement." Presentation: Montreal QC, Canada: Invited Address, SRCD Biennial Meeting, March 31 - April 2, 2011.
Presented: Washington DC: Innovative Research to Reduce Addiction, Trauma and Related Co-Morbidities, A Research Development & Technical Assistance Conference (NIDA, NICHD), November 1-2, 2010.
See above link: 44 slides.
Mandara, Jelani. "How Socialization Contributes to Gender Disparities in Health and Achievement." Presented: Washington DC: Innovative Research to Reduce Addiction, Trauma and Related Co-Morbidities, A Research Development & Technical Assistance Conference (NIDA, NICHD), November 1-2, 2010.
Objective. The purpose of this study was to assess the effects of parenting styles on Black, White, and Hispanic adolescents achievement test scores.
Design. A total of 3290 adolescents and their mothers from the National Longitudinal Survey of Youth were assessed on various measures of parenting, math and reading achievement, SES, cognitive stimulation, and child motivation and health. The study also used different measures of demandingness, less extreme classification criteria, more control variables, and a higher proportion of Black and Hispanic youth than in previous studies.
Results. Authoritative parenting was associated with high scores for all race and gender groups, even after the background factors were controlled. Authoritarian parenting was not as beneficial to African Americans or as detrimental to European Americans as in previous studies. Permissive and neglectful parenting styles were associated with lower test scores for all groups, especially for African Americans. Consequently, the race gap in achievement was non-existent for those with authoritative parents, but was rather dramatic for those with non-authoritative parents.
Conclusion. Baumrind's conception of authoritative parenting is optimal for all American race and gender groups' achievement. Parenting interventions that teach this conception of authoritative parenting should be the focus of family-based prevention interventions.
Mandara, Jelani. "The Effects of Parenting Styles on Adolescent Achievement Test Scores: Ethnic and Gender Differences (And Similarities)." Working Paper, School of Education and Social Policy, Northwestern University, 2006.
Presented: Cambridge, MA, Achievement Gap Initiative Conference, Harvard University, June 2006.
Intergenerational predictors of the Black-White achievement gap among 2108 adolescents from the NLSY were examined. The results showed that the gaps in SES and achievement significantly reduced over the past few generations. Moreover, grandparents' education and occupational prestige accounted for 20% of the achievement gap, but were completely mediated by parent and adolescent factors. Parents' SES, achievement, and parenting accounted for almost all of the remaining ethnic differences in math and reading scores. Parental demandingness and adolescent health and motivation had particularly large unique effects on achievement. It was concluded that adjusting for these differences across generations would, theoretically, all but eliminate the Black-White test score gap. The need for culturally specific parenting interventions was also discussed.
Mandara, Jelani, Nereira Greene and Fatima Varner. "Intergenerational Predictors of the Black-White Achievement Gap in Adolescence." Presented: Cambridge, MA, Achievement Gap Initiative Conference, Harvard University, June 2006.
Mandara, Jelani, Nereira Greene and Fatima Varner. "Intergenerational Predictors of the Black-White Achievement Gap in Adolescence." Working Paper, School of Education and Social Policy, Northwestern University, 2006.
Journal of Marriage and Family 73,3 (June 2011): 557–569.
The relationship between family structure and marijuana use throughout adolescence was assessed among 1,069 African Americans from the NLSY. A model was also tested suggesting that the effects of family structure on marijuana use would be mediated by poverty, neighborhood quality, and adolescents' self-control. As most prior studies have found, family structure was not related to female adolescents' marijuana use. For young men, being raised with both biological parents was associated with less marijuana use throughout adolescence compared to those whose mothers never married, divorced early and never remarried, or divorced and remarried. Some support for the model was also found. We concluded that being raised without the presence of a biological father is a risk factor for marijuana use among young men, but African American young women from single-parent households have unique resources that protect them from marijuana use. Understanding those resources may offer insight into prevention programs for other youth.
Mandara, Jelani, Sheba Y. Rogers and Richard E. Zinbarg. "The Effects of Family Structure on African American Adolescents' Marijuana Use." Journal of Marriage and Family 73,3 (June 2011): 557–569. A.
Journal of Educational Psychology 101,4 (November 2009): 867-878.
The authors examined intergenerational family predictors of the Black–White achievement gap among 4,406 adolescents from the National Longitudinal Survey of Youth. An intergenerational model of the process by which family factors contribute to the achievement gap was also tested. The results showed that the ethnic gaps in socioeconomic status (SES) and achievement had significantly reduced over the past few generations. Moreover, measures of grandparent SES, mothers' achievement, parent SES, and a comprehensive set of reliable parenting practices explained all of the ethnic differences in achievement scores. Parenting practices such as creating a school-oriented home environment, allowing adolescents to make decisions, and not burdening them with too many chores had particularly important effects on the achievement gap. The authors conclude that adjusting for these differences would eliminate the ethnic achievement gap.
Mandara, Jelani, Fatima Varner, Nereira Greene and Scott Richman. "Intergenerational Family Predictors of the Black–White Achievement Gap." Journal of Educational Psychology 101,4 (November 2009): 867-878.


Helen's career started in the United States Navy as a Hospital Corpsman. Highlights include serving on the USNS Comfort during Operation Desert Storm followed by a special assignment with the United States Marine Corp in Quantico, VA. After 4 years of honorable service, including a Navy Achievement Medal, she began her civilian career working for Concentra, Inc., the country's largest provider of occupational health care. She was promoted several times and acquired critical leadership skills in health care, operations, sales, government contracting and mergers, and acquisitions.
She has spent the last ten years as a consultant on a wide variety of business strategy topics ranging from Governance and Sustainability to Employee Engagement and Diversity & Inclusion.
While at Gallup, Inc., she managed several large-scale research projects for the Department of Veterans Affairs, Department of Defense, and the United State Air Force, among others. Her time at The Conference Board presented numerous opportunities to collaborate with Fortune 500 C-Suite executives. In this role, Helen focused on solution selling by matching The Conference Board's portfolio of extensive enterprise-wide knowledge assets to succinct client needs. Throughout her career she has won several customer experience awards and sold significant consulting engagements to many of the world's largest brands.
She received her undergraduate degree from La Salle University with a concentration in Finance and her MBA from Cleveland State University. She is currently pursuing her second graduate degree part-time in Information Technology with a concentration in Cyber Security through Virginia Tech's MIT program. Known for her ethics, integrity, and accountability, Helen's core philosophy in life is to always focus on doing the right thing.


For a few months now, ExxonMobil has been hit by a series of politically motivated legal attacks related to our climate research.
Amid all the tumult, it's easy to lose track of the most elemental – if not the most important – facts about our corporation's position on climate change.
So let me take this opportunity to restate it.
At ExxonMobil, we believe the risks of climate change are real.
We are actively working to reduce greenhouse emissions in our own operations and to help our customers reduce their emissions as well.
That means developing technologies that reduce emissions, including working to improve energy efficiency and advance cogeneration. In fact, our cogeneration facilities alone enable the avoidance of approximately 6 million metric tons of greenhouse gas emissions each year, and allow us to feed power back to the grid in certain instances.
We are also developing next-generation biofuels that don't compete with food and water resources. Much of this research is conducted through partnerships with leading universities and research institutions including the Colorado School of Mines, Michigan State, Northwestern University, and the University of Wisconsin.
Meanwhile, we are advancing conventional carbon-capture-and-storage technology while at the same time pursuing innovative carbon-capture solutions involving carbonate fuel cells. This far-sighted research aims to reduce the cost of carbon capture while keeping CO2 out of the atmosphere.
All told, since 2000, ExxonMobil has spent approximately $7 billion to develop lower-emission energy solutions.
That figure doesn't include the fact that as the nation's leading producer of natural gas, ExxonMobil has helped contribute to the overall drop in energy-related CO2 emissions over the past decade.
As policymakers develop mechanisms to meet the goals set in Paris, they are expected to focus on reducing the greatest amount of emissions at the lowest cost to society. At the same time, they should recognize important shared humanitarian needs, including providing reliable and affordable energy to improve living standards.
As a global issue, addressing the risks of climate change requires broad-based, practical solutions around the world.
Of the policy options being considered by governments, we believe a revenue-neutral carbon tax is the best option to fulfill these principles.
To read more about ExxonMobil's efforts to address the risks of climate change, please visit our corporate website.


This paintings, up-to-date through Walter P. Unger, a well-known global authority, examines and places into standpoint fresh cutting edge surgical suggestions and significant advancements of the verified equipment for hair recovery and reconstruction which produce much better effects. This version bargains a list of latest instrumentation and their assets, a brand new part at the standardization of hair images, enormously multiplied assurance of normal rules of recipient website association and making plans, and masses extra.
Evidence-based, peer reviewed, best-practice administration guidance for dermatologistsIncorporates the fundamental guidance which were accelerated with additional fabric including:Web tackle for the guidelineEditorial commentLinks to extra directions from different foreign organizationsLinks to the BAD's patient-information leafletsOther patient-oriented info.
This publication encompasses all the state of the art options at present to be had for the care of burn sufferers. ready with a spotlight on schooling and coaching, this striking consultant offers the newest recommendations and breakthroughs for the care of burn sufferers in outpatient, working room, and in depth care unit settings and introduces the entire proper info required to use the most recent applied sciences to the care of burn sufferers utilizing a hands-on method.
Discusses the reasons and remedy of zits.
8)5. 9)7–9,13. Melanosis differs from fibrosis by the additional presence of a band of melanophages in a thickened papillary dermis9,13. 11). Other vascular dermoscopic structures include telangiectasia which represent dilated vessels in the papillary dermis and redblue areas (lacunae) which correspond to dilated vascular spaces in the dermis. Sometimes milialike cysts are pigmented, and thus can resemble globules (see Chapter 6b). Histopathologically, comedolike structures correspond to the concave, often hyperkeratinized clefts, of the epidermis (see Chapter 6b).
Histopathologically, they represent nests of pigmented epithelial nodules of basal cell carcinoma (see Chapter 6a). Histopathologically, they correspond to the nests of basal cell carcinoma radiating from a follicular epithelium (see Chapter 6a). When a network is absent, ovoid nests are highly suggestive of basal cell carcinoma (see Chapter 6a). They have to be differentiated from multiple bluegray dots (which correspond to melanophages and melanin dust; see Chapter 6a). Superficial black network: an additional dermoscopic clue for the diagnosis of pigmented spindle and/or epithelioid cell nevus.


Joined by cast mates Bruce Willis and Samuel L. Jackson as well as director M. Night Shyamalan, Paulson and McAvoy goof around on the white carpet at the Curzon Mayfair.
AceShowbiz - Sarah Paulson and James McAvoy apparently share the same sense of humor. Hitting the premiere of their new movie "Glass" in London, England on Wednesday, January 9, they lit up the icy-white carpet with their hilarious interaction.
The two were seen goofing around while posing together for photographers at the venue, the Curzon Mayfair. The "American Horror Story" actress was making a face while pointing her two index fingers up, and McAvoy followed by making a bewildered expression.
Paulson and McAvoy were joined by cast mates Bruce Willis and Samuel L. Jackson as well as director M. Night Shyamalan. Paulson, McAvoy, Jackson and Shyamalan wore something purple to match the event's color theme.
Paulson's something purple was her dress. She wore a cream jacket over her strapless pinkish-purple gown, with flame-like green and yellow detail around the hem. She went bolder with her hair, which was styled into several knots.
Jackson opted for an all-purple look consisting of a turtleneck shirt, velvet suit and pants, as well as matching woolly hat. McAvoy wore a purple shirt, while and Shyamalan added a touch of purple with his tie.
A sequel to "Split", "Glass" bring back Willis' and Jackson's "Unbreakable" characters David Dunn and Elijah Price / Mr. Glass, respectively. According to the synopsis, Dunn pursues McAvoy's The Beast in a series of escalating encounters, while the shadowy presence of Price emerges as an orchestrator who holds secrets critical to both men.
Paulson stars as Dr. Ellie Staple, a psychiatrist specializing in delusions of grandeur who treats patients convinced they are superhuman beings. Anya Taylor-Joy additionally returns as Casey Cooke, a young girl who was kidnapped by one of Kevin's personalities as a potential sacrifice to The Beast and survived in "Split".
The movie is set to open in U.S. theaters on January 18.
Sarah Paulson looked stunning in a strapless pinkish-purple gown with flame-like green and yellow detail around the hem.
The Emmy-winning actress went bolder with her hair, tying it into several knots.
James McAvoy oozed a gentleman look in a navy suit and plum shirt.
The two actors joked around on the icy-white carpet.
Paulson and McAvoy were joined by Samuel L. Jackson and M. Night Shyamalan for a group photo.
Jackson stood out in his bright purple outfit.
Bruce Willis went for a navy suit, a white shirt and a blue-and-white dotted tie.
Co-star Anya Taylor-Joy wore a cute black dress with a matching headband.


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Roberto Dell'Acqua (Roma, 16 de abril de 1946-Roma, 16 de septiembre de 2019) fue un actor italiano.

Biografía
Hermano de Arnaldo Dell'Acqua, Ottaviano Dell'Acqua y Alberto Dell'Acqua, (los tres son actores) y de Fernanda Dell'Acqua (que no se dedica a la actuación). En 1979, los cuatro hermanos interpretan a un grupo de zombis en la isla de Matool, en la película Zombi 2, dirigida por Lucio Fulci, donde actúa Al Cliver, Ian McCulloch, Olga Karlatos, Stefania D'Amario y Auretta Gay.

Roberto Dell'Acqua participó en 52 producciones aproximadamente iniciando en 1970, y visto últimamente en 1990.

Filmografía
 Buon funerale amigos!... paga Sartana, de Giuliano Carnimeo (1970)
 Ciakmull - L'uomo della vendetta, de Enzo Barboni (1970)
 Lo chiamavano Trinità..., de Enzo Barboni (1970)
 Quel maledetto giorno della resa dei conti, de Sergio Garrone (1971)
 Continuavano a chiamarlo Trinità, de Enzo Barboni (1971)
 Eroi all'inferno, de Joe D'Amato (1973)
 Piedone lo sbirro, de Steno (1973)
 I racconti di Viterbury - Le più allegre storie del '300, de Mario Caiano (1973)
 Il mio nome è Shangai Joe, de Mario Caiano (1973)
 Piedone a Hong Kong, de Steno (1975)
 Colpo in canna, de Fernando Di Leo (1975)
 Che botte ragazzi!, de Bitto Albertini (1975)
 Keoma, de Enzo G. Castellari (1976)
 Il grande racket, de Enzo G. Castellari (1976)
 Napoli violenta, de Umberto Lenzi (1976)
 La via della droga, de Enzo G. Castellari (1977)
 Lo chiamavano Bulldozer, de Michele Lupo (1978)
 Zombi 2, de Lucio Fulci (1979)
 Incubo sulla città contaminata, de Umberto Lenzi (1980)
 ...E tu vivrai nel terrore! L'aldilà, de Lucio Fulci (1981)
 Dos granujas en el Oeste, de Michele Lupo (1981)
 I giorni dell'inferno, de Tonino Ricci (1986)
 Killer vs. Killers, de Fernando Di Leo (1985)
 L'ultimo volo all'inferno, de Ignazio Dolce (1990)

Referencias

Enlaces externos
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Actores del siglo XX
Actores del siglo XXI
Actores de televisión de Italia
Actores de cine de Italia
Nacidos en Roma
Fallecidos en Roma

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Jack Russell Terrier Breed Characteristics
Jack Russell's Breed History
The Jack Russell Terrier (JRT), Parson Russell Terrier, or Jack Russell as it is affectionately known; has a long and distinguished past. That past, however, is shrouded in mystery. One thing we know for sure is that the terrier began its life hunting rats in the castles of England more than one thousand years ago. The Jack Russell evolved from the terriers of that time period as sporting events such as badger baiting and rat killing blossomed in popularity. It's not clear when the transition to todays Jack Russell occurred, but it is clear that Parson John Russell played a large role.
John Russell was a clergyman known for his love of hunting, and his preference for terrier breeds. Legend has it that John "Parson Jack" purchased a terrier named Trump from a milkman because the dog embodied all that he sought in a hunting terrier. Jack went on to breed the terrier to meet his specifications, and not those of dog show breeders of the time. Though it's not clear how closely his terriers resembled the current day Jack Russell that bares his name, after his death in 1833 all white terriers with similar markings were dubbed Jack Russell Terriers.
The Parson Russell Personality
If nothing else, one defining characteristic bred into Jack Russell's has endured the test of time. Pason Jack believed that an important breed characteristic of his terriers was that they not be overly aggressive. Tenacity and courage are two qualities that most accurately define the Jack Russell, and coupled with Parson Jack's goal, the JRT is now a vivacious, playful, and energetic dog. The JRT should be confident and bold, but not nervous or aggressive.
Does the Jack Russell need a lot of grooming?
The exuberance of the Jack Russell breed translates to an adventurous spirit. Digging holes, squeezing through tiny spaces, and generally getting dirty is what makes this breed so much fun. For that reason, the JRT is often in need of grooming more than the average puppy. The Puppy Store always recommends regular bathing and brushing to get dogs used to the process. That way, when it becomes a necessity, it will be a pleasurable experience for you and your Parson Russell Terrier.
Do Jack Russell's need a lot of exercise?
As you can imagine, any dog that was bred to chase rats and foxes is not slouch when it comes to energy. Though most Jack Russell breeders are focused on looks and bloodlines, the liveliness and adventurous disposition is ever present. The JRT is a great dog for those with an active lifestyle, always eager to spend time with their owners regardless of the adventure. Jack Russells can do well living in an apartment, but long walks or regular dog park trips should be a priority. The Jack Russell Terrier, like all dogs, should be socialized from a young age and daily walks should be used to reinforce training.
Are Jack Russell's good family dogs?
The Parson Russell Terrier, if properly trained and socialized, can make a wonderful addition to any home. Older children are often a great match for the high energy spirit if the JRT, but the breed may resent younger children. The Jack Russell does not tolerate rough-and-tumble play, tail pulling, or general physical "molestation." It's imperative that younger children be taught to respect the breeds space, especially during feeding.
The dominant nature of most Jack Russell's means that socialization and training is of great significance if you intend to have other pets. Russell's can have good relationships with other dogs, but should always be monitored around cats, and never trusted around other small rodent like animals. Their nature is to hunt smaller animals, cats and gerbils certainly fall into that category. All dogs have unique and inherent personalities. Of course there are some exceptions to the rule, but ultimately it's important to understand what makes each breed a good fit for your family.
If you have any questions about Jack Russell Terrier puppies, and how one would fit with your family, please contact us for more information. Our puppy specialists will help you decide whether the JRT is right for you. You can also take our perfect puppy quiz to find the best dog for your unique personality and lifestyle. When you're ready to find you next four-legged friend, stop by to meet the puppy of your dreams, we're open 7 days a week.
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