CDT1

Gene Summary

Gene:CDT1; chromatin licensing and DNA replication factor 1
Aliases: DUP, RIS2
Location:16q24.3
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA replication factor Cdt1
Source:NCBIAccessed: 11 March, 2017

Ontology:

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 (1992-2017)
Graph generated 11 March 2017 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.

  • Protein Binding
  • Restriction Fragment Length Polymorphism
  • Cell Proliferation
  • Protein Stability
  • Promoter Regions
  • DNA Damage
  • Nucleic Acid Hybridization
  • Cullin Proteins
  • Cell Line
  • Cell Survival
  • Minichromosome Maintenance Complex Component 2
  • Mutation
  • Nuclear Proteins
  • Geminin
  • Apoptosis
  • Cyclopentanes
  • Xenograft Models
  • MicroRNAs
  • Gene Expression
  • DNA-Binding Proteins
  • Ubiquitin-Protein Ligases
  • RNA Interference
  • Prostate Cancer
  • Genomic Instability
  • DNA Replication
  • S Phase
  • Transfection
  • Skin Cancer
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • CDKN1A
  • Cell Cycle
  • Down-Regulation
  • Mice, Transgenic
  • Chromosome 16
  • Cell Cycle Proteins
  • Ubiquitins
  • Pyrimidines
  • Young Adult
Tag cloud generated 11 March, 2017 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)

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.

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.

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.

Tzetis M, Stefanaki K, Syrmou A, et al.
An unusual case of Cat-Eye syndrome phenotype and extragonadal mature teratoma: review of the literature.
Birth Defects Res A Clin Mol Teratol. 2012; 94(7):561-6 [PubMed] Related Publications
BACKGROUND Cat-Eye syndrome (CES) with teratoma has not been previously reported. We present the clinical and molecular findings of a 9-month-old girl with features of CES and also a palpable midline neck mass proved to be an extragonadal mature teratoma, additionally characterized by array comparative genomic hybridization (aCGH). RESULTS High resolution oligonucleotide-based aCGH confirmed that the supernumerary marker chromosome (SMC) derived from chromosome 22, as was indicated by molecular cytogenetic analysis with fluorescence in situ hybridization (FISH). Additionally, aCGH clarified the size, breakpoints, and gene content of the duplication (dup 22q11.1q11.21; size:1.6 Mb; breakpoints: 15,438,946-17,041,773; hg18). The teratoma tissue was also tested with aCGH, in which the CES duplication was not found, but the analysis revealed three aberrations: del Xp22.3 (108,864-2788,689; 2.7 Mb hg18), dup Yp11.2 (6688,491-7340,982; 0.65 Mb, hg18), and dup Yq11.2q11.23 (12,570,853-27,177,133; 14.61 Mb, hg18). These results indicated 46 XY (male) karyotype of the teratoma tissue, making this the second report of mature extragonadal teratoma in a female neonate, probably deriving from an included dizygotic twin of opposite sex (fetus in fetu). CONCLUSIONS Our findings extend the phenotypic spectrum of CES syndrome, a disorder with clinical variability, pointing out specific dosage-sensitive genes that might contribute to specific phenotypic features.

Georgin-Lavialle S, Lhermitte L, Suarez F, et al.
Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.
Eur J Haematol. 2012; 89(1):47-52 [PubMed] Related Publications
OBJECTIVE: Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c-Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c-Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis.
PATIENT AND METHODS: We describe here a patient with mast cell leukemia characterized by 42% of circulating mast cells associated with a previously unidentified c-Kit mutation in adult mastocytosis: dup(501-502).
MAIN FINDINGS: This patient was treated with masitinib, a novel c-Kit tyrosine kinase inhibitor, with a dramatic response observed following 3 months of treatment, including clinical improvement, disappearance of circulating mast cells, and decrease in both serum histamine and tryptase levels. In vitro and ex vivo research was performed on the patient's cells and revealed constitutive c-Kit phosphorylation in mast cell leukemia.
CONCLUSIONS: This case highlights the importance of sequencing all c-Kit exons when the classical D816V c-Kit mutation is not found, even in adults with SM. It also indicates that masitinib may be safe and effective for the treatment for some mast cell leukemia.

Pierini V, Nofrini V, La Starza R, et al.
Double CEBPE-IGH rearrangement due to chromosome duplication and cryptic insertion in an adult with B-cell acute lymphoblastic leukemia.
Cancer Genet. 2011; 204(10):563-8 [PubMed] Related Publications
In an adult case of B-cell acute lymphoblastic leukemia (B-ALL) with a complex karyotype, both chromosomes 14 were involved in unbalanced rearrangements, specifically, der(14)t(13;14)(q21;q21) and dup(14)(q11q32). Fluorescence in situ hybridization (FISH) detected two CEBPE-IGH rearrangements at the dup(14). One was found at the duplication breakpoint and the other derived from insertion of CEBPE into an apparently normal IGH locus. Hypotheses to account for these unusual chromosomal rearrangements are discussed. This case provides the first evidence that chromosome duplication and cryptic insertion produce the CEBPE-IGH fusion and that more than one CEBPE-IGH recombination can occur in a leukemic cell. Our findings confirm that deregulated CEBPE plays a crucial role in the pathogenesis of CEBPE-IGH positive B-ALL.

Lundin C, Hjorth L, Behrendtz M, et al.
High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome.
Genes Chromosomes Cancer. 2012; 51(2):196-206 [PubMed] Related Publications
Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.

Cho JH, Hur M, Moon HW, et al.
Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature.
Hum Pathol. 2012; 43(4):605-9 [PubMed] Related Publications
Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.

Zhang KH, Li GL, Liu ZZ
Expressions of cell cycle associated factors geminin and cdt1 in patients with acute leukemia.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011; 19(3):578-81 [PubMed] Related Publications
The purpose of this study was to detect the expression levels of geminin and cdt1 in peripheral blood and bone marrow from patients with newly diagnosed acute leukemia (AL), and further explore effects of them in the pathogenesis of AL. mRNA expression of geminin and cdt1 in peripheral blood and bone marrow of newly diagnosed AL patients was detected by SYBR Green real-time quantitative reverse transcription polymerase chain reaction(SYBR-RT-PCR). The results showed that mRNA expressions of both geminin and cdt1 in peripheral blood were positive in 10 out of 13 newly diagnosed ALL patients (76.92%) and in 9 out of 14 newly diagnosed AML patients (64.29%), while no positive expression of these 2 genes was detected in 10 normal controls; mRNA expression levels of geminin and cdt1 in bone marrow of newly diagnosed ALL and AML patients were 108.06 ± 67.34 and 52.37 ± 35.16, 62.66 ± 58.69 and 26.68 ± 22.29, respectively, which were higher than those in normal controls (11.81 ± 2.83 and 7.32 ± 5.77), there were significant differences (p < 0.01 and p < 0.05). mRNA expression of geminin was significantly positive related to mRNA expression of cdt1 in bone marrow of 34 newly diagnosed AL patients (r = 0.55, p < 0.01). It is concluded that mRNA expressions of geminin and cdt1 are enhanced and significantly positively related between them in bone marrow of AL patients. The over-expression of geminin and cdt1 mRNA may play an important role in pathogenesis of AL.

Liu R, Zhou Z, Zhao D, Chen C
The induction of KLF5 transcription factor by progesterone contributes to progesterone-induced breast cancer cell proliferation and dedifferentiation.
Mol Endocrinol. 2011; 25(7):1137-44 [PubMed] Related Publications
Progesterone (Pg) promotes normal breast development during pregnancy and lactation and increases the risk of developing basal-type invasive breast cancer. However, the mechanism of action of Pg has not been fully understood. In this study, we demonstrate that the mRNA and protein expression of Klf5, a pro-proliferation transcription factor in breast cancer, was dramatically up-regulated in mouse pregnant and lactating mammary glands. Pg, but not estrogen and prolactin, induced the expression of Krüpple-like factor 5 (KLF5) in multiple Pg receptor (PR)-positive breast cancer cell lines. Pg induced the KLF5 transcription through PR in the PR-positive T47D breast cancer cells. Pg-activated PR increased the KLF5 promoter activity likely through binding to a Pg response element at the KLF5 promoter. Importantly, Pg failed to promote T47D cell proliferation when the KLF5 induction was blocked by small interfering RNA. KLF5 is essential for Pg to up-regulate the expression of cell cycle genes, including CyclinA, Cdt1, and E2F3. In addition, KLF5 overexpression was sufficient to induce the cytokeratin 5 (CK5) expression, and the induction of CK5 by Pg was significantly reduced by KLF5 small interfering RNA. Consistently, the expression of KLF5 was positively correlated with that of CK5 in a panel of breast cancer cell lines. Taken together, we conclude that KLF5 is a Pg-induced gene that contributes to Pg-mediated breast epithelial cell proliferation and dedifferentiation.

Aggarwal P, Vaites LP, Kim JK, et al.
Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.
Cancer Cell. 2010; 18(4):329-40 [PubMed] Free Access to Full Article Related Publications
Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.

Chuang CK, Chuang KL, Hsieh CH, et al.
Epstein-Barr virus-infected cell line TCC36B derived from B lymphocytes infiltrating renal pelvis urothelial carcinoma.
Anticancer Res. 2010; 30(9):3473-8 [PubMed] Related Publications
UNLABELLED: This study reports an initial analysis of an EBV-infected B cell line (TCC36B), established from an urothelial carcinoma (UC) lesion of the renal pelvis.
MATERIALS AND METHODS: Cytofluorometric and G-banding analyses were performed for phenotyping and cytogenetics. PCR was used to detect EBV DNA, and sequence analysis to investigate mutations and deletions of the latent membrane protein (LMP)-1 gene of EBV.
RESULTS: TCC36B cells proliferated in vitro and showed positivity for surface CD19, CD20, HLA-DR and IgG(λ), indicating that they belong to B-cells. Cytogenetic analysis showed 46,XX with a unique clonal abnormality of dup(2)(p13p25). EBV DNA was detected in TCC36B cells. Sequence analysis revealed a 30-bp deletion and 7 point mutations on the LMP-1 gene in TCC36B cells.
CONCLUSION: These results suggest the involvement of an EBV variant in the pathogenesis of UC. This cell line should thus facilitate further investigations on the aetiological role of EBV in urothelial cancer.

Blom E, Heyning FH, Kroes WG
A case of angioimmunoblastic T-cell non-Hodgkin lymphoma with a neocentric inv dup(1).
Cancer Genet Cytogenet. 2010; 202(1):38-42 [PubMed] Related Publications
Neocentromeres are rare epigenetic phenomena in which functional centromeres are formed onto novel chromosomal locations without any alpha-satellite DNA. To date, constitutional human neocentromeres have been reported in at least 90 cases. In cancer, however, the knowledge is much more limited. Acquired neocentromeres have been described in a particular class of lipomatous tumors (atypical lipomas and well-differentiated liposarcomas; ALP-WDLPS), three cases of acute myeloid leukemia (AML), one case of non-Hodgkin lymphoma (NHL), and one case of lung carcinoma. Here, we report on a 66-year-old male with angioimmunoblastic T-cell NHL. Cytogenetic analysis of his bone marrow showed multiple aberrations, including the presence of a supernumerary chromosome. Using the fluorescence in situ hybridization technique, the supernumerary chromosome was demonstrated to be entirely composed of material derived from chromosome 1. It represented an inverted duplication of the segments between 1q21 and 1qter with a neocentromere in band 1q31. To our knowledge, this is the second reported case of NHL (both T-cell) with the presence of a neocentromere. The occurrence of neocentromeres in tumor cells, however, may be underestimated because of technical limitations during the routine diagnostic chromosomal analysis. The prognostic impact is therefore currently unknown.

Pienkowska-Grela B, Rymkiewicz G, Grygalewicz B, et al.
Partial trisomy 11, dup(11)(q23q13), as a defect characterizing lymphomas with Burkitt pathomorphology without MYC gene rearrangement.
Med Oncol. 2011; 28(4):1589-95 [PubMed] Related Publications
Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma characterized by specific morphological and immunophenotypic features. The basic genetic feature of BL is the rearrangement of MYC gene, visible as t(8;14)(q24;q32) translocation or its variant. However, some lymphomas with characteristic BL morphology are nowadays diagnosed as B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL (Inter-DLBCL/BL) for biological or clinical reasons. We present four lymphomas without the MYC rearrangement presented typical Burkitt morphology, FCM immunophenotype with some deviations when compared to a typical BL. The cases were finally diagnosed as Inter-DLBCL/BL. All of them presented a recurrent abnormality within the chromosome 11: dup(11)(q23q13). We suppose that the dup(11)(q23q13), in absence of the MYC gene rearrangement, is connected with borderline lymphomas with a morphology similar or identical to that of the Burkitt lymphoma. Identifying such an aberration may be helpful in the diagnostics of Inter-DLBCL/BL eventually forming a distinct subgroup of lymphomas.

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