Gene Summary

Gene:CDT1; chromatin licensing and DNA replication factor 1
Aliases: DUP, RIS2
Summary:The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein. [provided by RefSeq, Mar 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA replication factor Cdt1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 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.

  • DNA-Binding Proteins
  • DNA Damage
  • Restriction Fragment Length Polymorphism
  • Geminin
  • Cullin Proteins
  • Cell Proliferation
  • RNA Interference
  • Minichromosome Maintenance Complex Component 2
  • Gene Expression Regulation
  • DNA Replication
  • Cell Survival
  • S Phase
  • Cell Cycle
  • Chromosome 16
  • Promoter Regions
  • Cell Line
  • Gene Expression
  • Apoptosis
  • Messenger RNA
  • Histones
  • Skin Cancer
  • Nucleic Acid Hybridization
  • Mice, Transgenic
  • Prostate Cancer
  • Antineoplastic Agents
  • Cyclopentanes
  • Cancer Gene Expression Regulation
  • CDKN1A
  • Protein Stability
  • Nuclear Proteins
  • Genomic Instability
  • Down-Regulation
  • Young Adult
  • Transfection
  • Neoplastic Cell Transformation
  • Ubiquitin-Protein Ligases
  • Cell Cycle Proteins
  • MicroRNAs
  • Mutation
  • Pyrimidines
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: CDT1 (cancer-related)

Gunnarsson R, Dilorenzo S, Lundin-Ström KB, et al.
Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia.
Leukemia. 2018; 32(10):2117-2125 [PubMed] Free Access to Full Article Related Publications
High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

Yu Z, Wang R, Chen F, et al.
Five Novel Oncogenic Signatures Could Be Utilized as AFP-Related Diagnostic Biomarkers for Hepatocellular Carcinoma Based on Next-Generation Sequencing.
Dig Dis Sci. 2018; 63(4):945-957 [PubMed] Related Publications
BACKGROUND: Alpha-fetal protein (AFP) is an important conventional clinical diagnostic indicator of hepatocellular carcinoma (HCC). However, the utilization of AFP alone might yield deceptive results due to its limited sensitivity and accuracy.
AIMS: Our study was designed to investigate latent diagnostic biomarkers that could function as auxiliary clinical indicators of HCC and enhance the accuracy of joint diagnosis with AFP.
METHODS: We analyzed gene expression profiles and clinical data from HCC patients in The Cancer Genome Atlas database. Differentially expressed genes were identified, and a gene set enrichment analysis was conducted to uncover their biological functions and molecular processes. A weighted correlation network analysis and a protein-protein interaction analysis were performed to detect AFP-related biomarkers. The diagnostic performance of these biomarkers was verified using datasets from the GEO database. A diagnostic nomogram was established using the expression levels of potential biomarkers. Quantitative real-time PCR was performed using tissues from 16 HCC patients to validate the results.
RESULTS: Five AFP-related diagnostic biomarkers, CDT1, MCM7, NUDT1, CENPM, and HDAC11, were discovered. The diagnostic performance of these biomarkers and the nomogram were demonstrated to be excellent according to receiver operating characteristic curves. CDT1, MCM7, and NUDT1 were shown to be up-regulated in HCC tissues through quantitative real-time PCR.
CONCLUSIONS: We discovered five diagnostic biomarkers and established a nomogram as a complement to AFP in the diagnosis of HCC. Our results provide a more accurate diagnostic plan for HCC patients based on next-generation sequencing compared with AFP alone.

Vanderdys V, Allak A, Guessous F, et al.
The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.
Mol Cancer Ther. 2018; 17(2):368-380 [PubMed] Free Access to Full Article Related Publications
The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.

Capela de Matos RR, Ney Garcia DR, Cifoni E, et al.
GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High-Resolution Molecular Cytogenetic Studies.
Cytogenet Genome Res. 2017; 152(1):33-37 [PubMed] Related Publications
Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases. Here, we describe a 7- month-old girl with a history of fever and severe diarrhea, and a physical examination remarkable for pallor and hepatosplenomegaly. A novel complex hyperdiploid karyotype 53,XX,+X,+6,t(9;11)(p21.3;q23.3),+der(9)t(9;11)(p21.3;q23.3),dup(13)(q31q34),+14,+19,+21,+22 was characterized by high-resolution molecular cytogenetic approaches. Fluorescence in situ hybridization, multiplex-FISH, and multicolor chromosome banding were applied, revealing 2 reverse MLLT3-KMT2A fusions and a duplication of the GAS6 oncogene. Our work suggests that molecular cytogenetic studies are crucial for the planning of a proper strategy for risk therapy in AML infants with hyperdiploid karyotypes.

Mahadevappa R, Neves H, Yuen SM, et al.
The prognostic significance of Cdc6 and Cdt1 in breast cancer.
Sci Rep. 2017; 7(1):985 [PubMed] Free Access to Full Article Related Publications
DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients.

van Kempen LC, Redpath M, Elchebly M, et al.
The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene.
Sci Transl Med. 2016; 8(369):369ra177 [PubMed] Related Publications
Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.

Zhang R, Wu J, Ferrandon S, et al.
Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing.
Oncotarget. 2016; 7(49):80190-80207 [PubMed] Free Access to Full Article Related Publications
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter. Pretreatment of HT29 cells with α-amanitin reduced GANT61-induced γH2AX foci. Co-localization of GLI1 and BrdU foci, inhibited by GANT61, indicated GLI1 and DNA replication to be linked. By co-immunoprecipitation and confocal microscopy, GLI1 co-localized with the DNA licensing factors ORC4, CDT1, and MCM2. Significant co-localization of GLI1 and ORC4 was inhibited by GANT61, and enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter. CDT1 was found to be a transcription target of GLI1. Overexpression of CDT1 in HT29 and SW480 cells reduced GANT61-induced cell death, gH2AX foci, and cleavage of caspase-3. Data demonstrate involvement of transcription and of DNA replication licensing factors by non-transcriptional and transcriptional mechanisms in the GLI-dependent mechanism of action of GANT61.

Wong KM, Micel LN, Selby HM, et al.
Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924).
Invest New Drugs. 2017; 35(1):11-25 [PubMed] Free Access to Full Article Related Publications
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC

Jing P, Cao S, Xiao S, et al.
Enhanced growth inhibition of prostate cancer in vitro and in vivo by a recombinant adenovirus-mediated dual-aptamer modified drug delivery system.
Cancer Lett. 2016; 383(2):230-242 [PubMed] Related Publications
The peptide aptamer DUP-1 targets prostate-specific membrane antigen (PSMA)-negative cells, while the RNA aptamer A10-3.2 targets PSMA-positive prostate cancer cells. Moreover, the tumor-suppressor gene phosphatase and tensin homolog (PTEN) and the chemotherapeutic agent doxorubicin (DOX) effectively inhibit prostate cancer, and a recombinant adenovirus (Ad5) mediates high gene transfer efficiency. Here, we design a dual-aptamer modified tumor targeting gene and DOX delivery system mediated by recombinant adenovirus (A10-3.2(DOX)/DUP-1-PEG-Ad5, ADDP-Ad5). DUP-1 and A10-3.2 are connected to the adenovirus through polyethylene glycol (PEG), PTEN is integrated into Ad5, and DOX is embedded into the double chain of aptamer A10-3.2. The PEG-modification rate of Ad5 is 98.70 ± 2.43%. The DUP-1 and A10-3.2 modified products yield 80.40 ± 1.36% and 82.20 ± 2.14%, respectively. The uptake of ADDP-Ad5 and the expression of the reporter gene are enhanced by the system in PSMA-positive LNCaP and PSMA-negative PC3 human prostate cancer cells. ADDP-Ad5 significantly inhibits the cell growth of both LNCaP and PC3 cells. More importantly, ADDP-Ad5 is active in vivo against LNCaP and PC3 tumor xenografts and exhibits no significant toxicity to the mice. Therefore, ADDP-Ad5 may have clinical potential in prostate cancer therapy.

Kushwaha PP, Rapalli KC, Kumar S
Geminin a multi task protein involved in cancer pathophysiology and developmental process: A review.
Biochimie. 2016; 131:115-127 [PubMed] Related Publications
DNA replicates in a timely manner with each cell division. Multiple proteins and factors are involved in the initiation of DNA replication including a dynamic interaction between Cdc10-dependent transcript (Cdt1) and Geminin (GMNN). A conformational change between GMNN-Cdt1 heterotrimer and heterohexamer complex is responsible for licensing or inhibition of the DNA replication. This molecular switch ensures a faithful DNA replication during each S phase of cell cycle. GMNN inhibits Cdt1-mediated minichromosome maintenance helicases (MCM) loading onto the chromatin-bound origin recognition complex (ORC) which results in the inhibition of pre-replication complex assembly. GMNN modulates DNA replication by direct binding to Cdt1, and thereby alters its stability and activity. GMNN is involved in various stages of development such as pre-implantation, germ layer formation, cell commitment and specification, maintenance of genome integrity at mid blastula transition, epithelial to mesenchymal transition during gastrulation, neural development, organogenesis and axis patterning. GMNN interacts with different proteins resulting in enhanced hematopoietic stem cell activity thereby activating the development-associated genes' transcription. GMNN expression is also associated with cancer pathophysiology and development. In this review we discussed the structure and function of GMNN in detail. Inhibitors of GMNN and their role in DNA replication, repair, cell cycle and apoptosis are reviewed. Further, we also discussed the role of GMNN in virus infected host cells.

Sever E, Döğer E, Kumbasar S, et al.
Chromosome aberrations [dup(1q)] in endometrial cancer: Gene analysis of 54 surgical specimens in Turkey.
Taiwan J Obstet Gynecol. 2016; 55(3):357-62 [PubMed] Related Publications
OBJECTIVE: We aimed to evaluate the frequency of chromosomal aberrations and mutations in the k-ras or Her-2/neu genes in surgical specimens of endometrial carcinoma and their association with clinicopathological findings.
MATERIALS AND METHODS: Fifty-four patients who were treated for endometrial cancer between April 2010 and May 2011 at the Kocaeli University Obstetrics and Gynecology Department, Kocaeli, Turkey were enrolled in a prospective study. Clinical and histopathological findings were recorded. Genetic analysis, which included the detection of chromosomal deletions and duplications, as well as k-ras and Her-2/neu mutations, was performed on endometrial samples from surgical specimens.
RESULTS: In 70% of cases, tumor size was >2 cm or covered the entire uterine cavity, affecting mostly corpus (76%) and invading less than half of the myometrium (80%). Forty-six cases (86%) had endometrioid-type carcinoma, and early stage (Stage I, 65%) and higher grade (Grade II-III, 66%) tumors were predominant. Lymph node and lymphovascular involvement was positive in 11% and 28% of the patients, respectively. Chromosomal aberrations (deletion or duplication) and Her-2/neu and k-ras mutations were encountered in 44%, 15%, and 13% of surgical specimens, respectively. The most common chromosomal aberration was dup(1q) (n = 16). Oncogenic mutations in Her-2/neu or k-ras had no association with the severity of endometrial cancer, but the presence of chromosomal aberrations, as a whole or dup(1q) alone, were associated with higher tumor size, deeper myometrial invasion, advanced stage or grade, lymphovascular invasion, and lymph node involvement (p < 0.05 for all).
CONCLUSION: Chromosomal aberrations, particularly dup(1q), are related to advanced disease in endometrial cancer. Genetic analysis of cancer tissues may provide important insights in determining disease prognosis.

Benamar M, Guessous F, Du K, et al.
Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma.
EBioMedicine. 2016; 10:85-100 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle "rereplication" through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. CDT2 ablation inhibited a panel of melanoma cell lines through the induction of SET8- and p21-dependent DNA rereplication and senescence. Pevonedistat (MLN4924), a specific inhibitor of the NEDD8 activating enzyme (NAE), inhibits the activity of cullin E3 ligases, thereby stabilizing a vast number of cullin substrates and resulting in cancer cell inhibition in vitro and tumor suppression in nude mice. We demonstrate that pevonedistat is effective at inhibiting the proliferation of melanoma cell lines in vitro through the induction of rereplication-dependent permanent growth arrest as well as through a transient, non-rereplication-dependent mechanism. CRISPR/Cas9-mediated heterozygous deletion of CDKN1A (encoding p21) or SET8 in melanoma cells demonstrated that the rereplication-mediated cytotoxicity of pevonedistat is mediated through preventing the degradation of p21 and SET8 and is essential for melanoma suppression in nude mice. By contrast, pevonedistat-induced transient growth suppression was independent of p21 or SET8, and insufficient to inhibit tumor growth in vivo. Pevonedistat additionally synergized with the BRAF kinase inhibitor PLX4720 to inhibit BRAF melanoma, and suppressed PLX4720-resistant melanoma cells. These findings demonstrate that the CRL4-CDT2-SET8/p21 degradation axis is the primary target of inhibition by pevonedistat in melanoma and suggest that a broad patient population may benefit from pevonedistat therapy.
RESEARCH IN CONTEXT: The identification of new molecular targets and effective inhibitors is of utmost significance for the clinical management of melanoma. This study identifies CDT2, a substrate receptor for the CRL4 ubiquitin ligase, as a prognostic marker and therapeutic target in melanoma. CDT2 is required for melanoma cell proliferation and inhibition of CRL4(CDT2) by pevonedistat suppresses melanoma in vitro and in vivo through the induction of DNA rereplication and senescence through the stabilization of the CRL4(CDT2) substrates p21 and SET8. Pevonedistat also synergizes with vemurafenib in vivo and suppresses vemurafenib-resistant melanoma cells. These findings show a significant promise for targeting CRL4(CDT2) therapeutically.

Petrakis TG, Komseli ES, Papaioannou M, et al.
Exploring and exploiting the systemic effects of deregulated replication licensing.
Semin Cancer Biol. 2016; 37-38:3-15 [PubMed] Related Publications
Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.

Paiva C, Godbersen JC, Berger A, et al.
Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.
Cell Death Dis. 2015; 6:e1807 [PubMed] Free Access to Full Article Related Publications
Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

Tang NH, Toda T
MAPping the Ndc80 loop in cancer: A possible link between Ndc80/Hec1 overproduction and cancer formation.
Bioessays. 2015; 37(3):248-56 [PubMed] Free Access to Full Article Related Publications
Mis-regulation (e.g. overproduction) of the human Ndc80/Hec1 outer kinetochore protein has been associated with aneuploidy and tumourigenesis, but the genetic basis and underlying mechanisms of this phenomenon remain poorly understood. Recent studies have identified the ubiquitous Ndc80 internal loop as a protein-protein interaction platform. Binding partners include the Ska complex, the replication licensing factor Cdt1, the Dam1 complex, TACC-TOG microtubule-associated proteins (MAPs) and kinesin motors. We review the field and propose that the overproduction of Ndc80 may unfavourably absorb these interactors through the internal loop domain and lead to a change in the equilibrium of MAPs and motors in the cells. This sequestration will disrupt microtubule dynamics and the proper segregation of chromosomes in mitosis, leading to aneuploid formation. Further investigation of Ndc80 internal loop-MAPs interactions will bring new insights into their roles in kinetochore-microtubule attachment and tumourigenesis.

Günaldı M, Erkisi M, Afşar CU, et al.
Evaluation of endometrial thickness and bone mineral density based on CYP2D6 polymorphisms in Turkish breast cancer patients receiving tamoxifen treatment.
Pharmacology. 2014; 94(3-4):183-9 [PubMed] Related Publications
BACKGROUND: Several previous studies have examined the effect of CYP2D6 gene polymorphism on the efficacy and metabolism of tamoxifen (Tamoxifen Teva, Nolvadex) in the treatment of breast cancer. In the present study, the metabolic profiles associated with various CYP2D6 genotypes were evaluated.
METHOD: In the present study 92 Turkish breast cancer patients with early-stage hormone receptor-positive tumors treated with adjuvant tamoxifen (20 mg) were evaluated for CYP2D6 genotype and metabolic profiles. Known side effects of tamoxifen treatment, including endometrial thickening, changes in serum lipid levels and bone density, and hepatosteatosis, were evaluated according to the CYP2D6 polymorphism.
RESULT: The distribution of metabolic characteristics in the Turkish population was as follows: 77.1% normal metabolism, 11.5% intermediate metabolism, 5.2% ultrarapid metabolism, and 2.1% poor metabolism. The CYP2D6 genotypes associated with rapid metabolism were CYP2D6 3X*1/*1 duplication (DUP) and CYP2D6 2X*1/*2, while poor metabolism was associated with the genotypes CYP2D6 *3/*4 and CYP2D6 *6/*6. There was no statistically significant relationship between metabolic characteristics and bone density or hepatosteatosis. A statistically significant difference in total cholesterol and triglycerides was detected in lipid profile analysis (p = 0.003, p = 0.02). Assessment of endometrial thickness revealed a significant association of hyperplasia and poor metabolism, and an association between atrophy and ultrarapid metabolism (p = 0.01).
CONCLUSION: Significant development of endometrial hyperplasia was identified among individuals with poor tamoxifen metabolism. As a result, tamoxifen may be a significant predictor of endometrial thickening among individuals with poor metabolic characteristics.

McCann MJ, Rowland IR, Roy NC
The anti-proliferative effects of enterolactone in prostate cancer cells: evidence for the role of DNA licencing genes, mi-R106b cluster expression, and PTEN dosage.
Nutrients. 2014; 6(11):4839-55 [PubMed] Free Access to Full Article Related Publications
The mammalian lignan, enterolactone, has been shown to reduce the proliferation of the earlier stages of prostate cancer at physiological concentrations in vitro. However, efficacy in the later stages of the disease occurs at concentrations difficult to achieve through dietary modification. We have therefore investigated what concentration(s) of enterolactone can restrict proliferation in multiple stages of prostate cancer using an in vitro model system of prostate disease. We determined that enterolactone at 20 μM significantly restricted the proliferation of mid and late stage models of prostate disease. These effects were strongly associated with changes in the expression of the DNA licencing genes (GMNN, CDT1, MCM2 and 7), in reduced expression of the miR-106b cluster (miR-106b, miR-93, and miR-25), and in increased expression of the PTEN tumour suppressor gene. We have shown anti-proliferative effects of enterolactone in earlier stages of prostate disease than previously reported and that these effects are mediated, in part, by microRNA-mediated regulation.

Yang YL, Hung MS, Wang Y, et al.
Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
J Pathol. 2014; 233(2):113-23 [PubMed] Free Access to Full Article Related Publications
Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

Starr LJ, Sanmann JN, Olney AH, et al.
Occurrence of nephroblastomatosis with dup(18)(q11.2-q23) implicates trisomy 18 tumor screening protocol in select patients with 18q duplication.
Am J Med Genet A. 2014; 164A(4):1079-82 [PubMed] Related Publications
Duplications of the long arm of chromosome 18 have been previously reported in patients with phenotypic findings similar to full trisomy 18. Trisomy 18 increases the risk for Wilms tumor and it is currently recommended that these patients undergo abdominal ultrasonography screening every 6 months. We report on nephroblastomatosis in a 27-month-old male with a 55 Mb duplication of chromosome 18q11.2-q23 (chr18:22693370-77982126, hg 19) and propose that the trisomy 18 tumor screening protocol could also benefit patients with large 18q duplications.

Maria Murga Penas E, Schilling G, Behrmann P, et al.
Comprehensive cytogenetic and molecular cytogenetic analysis of 44 Burkitt lymphoma cell lines: secondary chromosomal changes characterization, karyotypic evolution, and comparison with primary samples.
Genes Chromosomes Cancer. 2014; 53(6):497-515 [PubMed] Related Publications
Burkitt lymphoma cell lines (BL-CL) are used extensively as in vitro models in genetic studies; however, cytogenetic information is not always available or updated. We provide a comprehensive cytogenetic resource of 44 BL-CL, assessed by G-banding, multicolor-FISH, and FISH with 1q, 3p, 7q, and 13q region-specific probes, including the first cytogenetic characterization of 22 BL-CL and the revision of further 22 commonly used BL-CL. Based on these data, we determined a consensus karyotype, evaluated in detail the secondary chromosomal changes (SCC), and the karyotypic stability of these cell lines. An individual karyotype was identified in all investigated BL-CL, confirming their unique origin. Most of the BL-CL remained cytogenetically relative stable after years of intensive cultivation. The most frequent structural SCC were dup(1q), del(13q) and the most frequent numerical SCC were +7, +13. Common breakpoints were located on 1q12, 7q11, and 13q31. The most common gains were in 1q and 7q and the most common losses were in 11q and 13q. Interestingly, the frequency of 1q gains and 13q losses was significantly higher in the EBV-negative than in the EBV-positive BL-CL. Furthermore, by reviewing karyotypes of 221 primary BL listed in the Mitelman database, we observed similarities between BL-CL and primary BL regarding the frequency of numerical and structural SCC and breakpoint distribution. In BL-CL and in primary BL two SCC, dup(1q), and +12, always occurred mutually exclusive of each other. These findings validate BL-CL as appropriate model for in vitro studies on the significance of SCC in the pathogenesis of BL.

Valovka T, Schönfeld M, Raffeiner P, et al.
Transcriptional control of DNA replication licensing by Myc.
Sci Rep. 2013; 3:3444 [PubMed] Free Access to Full Article Related Publications
The c-myc protooncogene encodes the Myc transcription factor, a global regulator of fundamental cellular processes. Deregulation of c-myc leads to tumorigenesis, and c-myc is an important driver in human cancer. Myc and its dimerization partner Max are bHLH-Zip DNA binding proteins involved in transcriptional regulation of target genes. Non-transcriptional functions have also been attributed to the Myc protein, notably direct interaction with the pre-replicative complex (pre-RC) controlling the initiation of DNA replication. A key component of the pre-RC is the Cdt1 protein, an essential factor in origin licensing. Here we present data suggesting that the CDT1 gene is a transcriptional target of the Myc-Max complex. Expression of the CDT1 gene in v-myc-transformed cells directly correlates with myc expression. Also, human tumor cells with elevated c-myc expression display increased CDT1 expression. Occupation of the CDT1 promoter by Myc-Max is demonstrated by chromatin immunoprecipitation, and transactivation by Myc-Max is shown in reporter assays. Ectopic expression of CDT1 leads to cell transformation. Our results provide a possible direct mechanistic link of Myc's canonical function as a transcription factor to DNA replication. Furthermore, we suggest that aberrant transcriptional activation of CDT1 by deregulated myc alleles contributes to the genomic instabilities observed in tumor cells.

Qiao D, Meyer K, Friedl A
Glypican 1 stimulates S phase entry and DNA replication in human glioma cells and normal astrocytes.
Mol Cell Biol. 2013; 33(22):4408-21 [PubMed] Free Access to Full Article Related Publications
Malignant gliomas are highly lethal neoplasms with limited treatment options. We previously found that the heparan sulfate proteoglycan glypican 1 (GPC1) is universally and highly expressed in human gliomas. In this study, we investigated the biological activity of GPC1 expression in both human glioma cells and normal astrocytes in vitro. Expression of GPC1 inactivates the G1/S checkpoint and strongly stimulates DNA replication. Constitutive expression of GPC1 causes DNA rereplication and DNA damage, suggesting a mutagenic activity for GPC1. GPC1 expression leads to a significant downregulation of the tumor suppressors pRb, Cip/Kip cyclin-dependent kinase inhibitors (CKIs), and CDH1, and upregulation of the pro-oncogenic proteins cyclin E, cyclin-dependent kinase 2 (CDK2), Skp2, and Cdt1. These GPC1-induced changes are accompanied by a significant reduction in all types of D cyclins, which is independent of serum supplementation. It is likely that GPC1 stimulates the so-called Skp2 autoinduction loop, independent of cyclin D-CDK4/6. Knockdown of Skp2, CDK2, or cyclin E, three key elements within the network modulated by GPC1, results in a reduction of the S phase and aneuploid fractions, implying a functional role for these regulators in GPC1-induced S phase entry and DNA rereplication. In addition, a significant activation of both the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways by GPC1 is seen in normal human astrocytes even in the presence of growth factor supplement. Both pathways are constitutively activated in human gliomas. The surprising magnitude and the mitogenic and mutagenic nature of the effect exerted by GPC1 on the cell cycle imply that GPC1 may play an important role in both glioma tumorigenesis and growth.

Pan WW, Zhou JJ, Yu C, et al.
Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer.
J Biol Chem. 2013; 288(41):29680-91 [PubMed] Free Access to Full Article Related Publications
Cullin-RING ubiquitin ligases (CRLs) are the largest family of E3 ligases and require cullin neddylation for their activation. The NEDD8-activating enzyme inhibitor MLN4924 reportedly blocked cullin neddylation and inactivated CRLs, which resulted in apoptosis induction and tumor suppression. However, CRL roles in ovarian cancer cell survival and the ovarian tumor repressing effects of MLN4924 are unknown. We show here that CRL4 components are highly expressed in human epithelial ovarian cancer tissues. MLN4924-induced DNA damage, cell cycle arrest, and apoptosis in ovarian cancer cells in a time- and dose-dependent manner. In addition, MLN4924 sensitized ovarian cancer cells to other chemotherapeutic drug treatments. Depletion of CRL4 components Roc1/2, Cul4a, and DDB1 had inhibitory effects on ovarian cancer cells similar to MLN4924 treatment, which suggested that CRL4 inhibition contributed to the chemotherapeutic effect of MLN4924 in ovarian cancers. We also investigated for key CRL4 substrate adaptors required for ovarian cancer cells. Depleting Vprbp/Dcaf1 did not significantly affect ovarian cancer cell growth, even though it was expressed by ovarian cancer tissues. However, depleting Cdt2/Dcaf2 mimicked the pharmacological effects of MLN4924 and caused the accumulation of its substrate, CDT1, both in vitro and in vivo. MLN4924-induced DNA damage and apoptosis were partially rescued by Cdt1 depletion, suggesting that CRL4(CDT2) repression and CDT1 accumulation were key biochemical events contributing to the genotoxic effects of MLN4924 in ovarian cancer cells. Taken together, these results indicate that CRL4(CDT2) is a potential drug target in ovarian cancers and that MLN4924 may be an effective anticancer agent for targeted ovarian cancer therapy.

Melo C, Gama-de-Sousa S, Almeida F, et al.
Cat eye syndrome and growth hormone deficiency with pituitary anomalies: a case report and review of the literature.
Gene. 2013; 529(1):186-9 [PubMed] Related Publications
Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted.

Hannah J, Zhou PB
The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies.
Chin J Cancer. 2013; 32(9):478-82 [PubMed] Free Access to Full Article Related Publications
Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cellular level, Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase's emergence as a potential driver of tumorigenesis.

Coulombe P, Grégoire D, Tsanov N, Méchali M
A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing.
Nat Commun. 2013; 4:2065 [PubMed] Related Publications
Cdt1 is required for loading the replicative DNA helicase MCM2/7, a process known as DNA replication licensing. Here we show that 129 mouse strains express a Cdt1 mutated allele with enhanced licensing activity. The mutation, named Δ(6)PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 Δ(6)PEST and more extensive deletions exhibit increased re-replication and transformation activities that are independent of the Geminin and E3 ligase pathways. This PEST domain negatively regulates cell cycle-dependent chromatin recruitment of Cdt1 in G2/M phases of the cell cycle. Mass spectrometry analysis indicates that Cdt1 is phosphorylated at sites within the deleted PEST domain during mitosis. This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity and suggests a mechanism by which the presence of Cdt1 in G2/M phases does not lead to premature origin licensing. These results also question the usage of 129 mouse strains for knockout analyses.

Dai Y, Chen S, Kmieciak M, et al.
The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair.
Mol Cancer Ther. 2013; 12(6):878-89 [PubMed] Free Access to Full Article Related Publications
Interactions between the novel Chk1 inhibitor MK-8776 and the histone deacetylase (HDAC) inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wt or -deficient leukemia cell lines, whereas p53 knockdown by short hairpin RNA (shRNA) sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S-phase checkpoint, disruption of DNA replication, and downregulation of proteins involved in DNA replication (e.g., Cdt1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced γ-H2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared with their wt counterparts and displayed downregulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary acute myelogenous leukemia (AML) blasts, particularly against the CD34(+)/CD38(-)/CD123(+) population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34(+) cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis, for example, p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy.

Liu NN, Ohkouchi M, Hashikura Y, et al.
Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503.
Lab Invest. 2013; 93(5):502-7 [PubMed] Related Publications
The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 μM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 μM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 μM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 μM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

Blank JL, Liu XJ, Cosmopoulos K, et al.
Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924.
Cancer Res. 2013; 73(1):225-34 [PubMed] Related Publications
MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription-coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G(2)-M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S-G(2) phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924.

Yamamoto K, Nakamachi Y, Yakushijin K, et al.
A novel TRB@/NOTCH1 fusion gene in T-cell lymphoblastic lymphoma with t(7;9)(q34;q34).
Eur J Haematol. 2013; 90(1):68-75 [PubMed] Related Publications
BACKGROUND: In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), activating mutations of NOTCH1 are observed in more than 50% of cases, whereas the t(7;9)(q34;q34) involving NOTCH1 at 9q34 and TRB@ at 7q34 is an extremely rare but recurrent translocation.
PATIENT: A 41-year-old male with a large mediastinal mass, pleural effusion, and lymphadenopathy was diagnosed as having T-LBL. Lymphoma cells were positive for CD4, CD8, CD2, CD3, CD5, CD7, CD10, and TdT.
RESULTS: G-banding and spectral karyotyping of pleural effusion cells showed 47,XY,dup(1)(q21q32),t(7;9)(q34;q34),+20. Genomic polymerase chain reaction (PCR) revealed that the 5' end of TRB@ J1-5 was connected with the middle of NOTCH1 exon 25 (434 bp downstream from its 5' end) in a 'head-to-head' configuration on the der(9)t(7;9), although nine extra bases were inserted between the two genes. Reverse transcription-PCR confirmed expression of the TRB@/NOTCH1 fusion transcripts. Similarly, the 5' end of J1-5 was fused to the shortened exon 25 with nine extra bases. The NOTCH1 breakpoint in exon 25 was very close to transcription start sites of deleted Notch1 in murine T-ALL.
CONCLUSIONS: The TRB@/NOTCH1 fusion gene with a NOTCH1 breakpoint in exon 25, which has not previously been detected in four other reported cases with t(7;9), could lead to aberrant expression of the truncated NOTCH1 by TRB@ enhancer elements. The resultant NOTCH1 receptor deleting most of the extracellular domain may be implicated in the pathogenesis of T-LBL by ligand-independent, constitutive activation of the NOTCH1 pathway, suggesting avenues for future therapy with γ-secretase inhibitors.

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