bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3098: Myc preferentially transforms hematopoietic stem cells into Precursor B cell lymphoblastic leukemia/lymphoma
Authors: Sugihara Eiji , Shimizu Takatsune , Ishizawa Jo , Okada Seiji , Miwa Masanao , Saya Hideyuki 
Published: February 2011

Abstract
Overexpression of Myc oncogenes (c-Myc, N-Myc and L-Myc) is frequently found in a wide range of tumors. Although many reports have shown that Myc can directly induce tumors in mice models, the cell-of-origin of the Myc-induced tumor is still unclear. In this study, we attempted to determine the cell-of-origin in the Myc-induced hematopoietic tumor by using bone marrow transplantation model. Bone marrow (BM) cells were harvested from 5FU-treated mice (6 to 8-week-old C57BL/6 mice) and then infected with retroviral vectors to express one of Myc genes, N-Myc. The infected cells were intravenously transplanted into irradiated syngenic mice. As a result, all mice transplanted with N-Myc-transduced BM cells died around 2 months. Those mice showed enlarged lymph nodes, splenomegaly and invaded livers. Abnormally increased WBCs in those mice showed B220+CD19+CD43+/−IgM−, indicating that enhanced expression of N-Myc in BM cells caused Precursor B cell lymphoblastic leukemia/lymphoma (Pre-B LBL). To determine the cell-of-origin of this tumor, the N-Myc-transduced BM cells were fractionated into hematopoietic stem cells (HSCs), committed lymphoid progenitors (CLPs) or myeloid progenitors (MPs) by cell sorter, and those fractions were transplanted into irradiated recipients. Limiting dilution analysis revealed that mice transplanted with HSCs had Pre-B LBL at significant higher frequencies (1:184) than mice transplanted with CLPs (1:558) or MPs (1:9286). Furthermore, to determine whether more lineage-committed cells can be directly the cell of origin, we sorted immature-B cells transduced with N-Myc from non-treated BM cells and transplanted those cells into recipients. While we could not obtain any tumors from those transplanted mice, mice transplanted with immature-B (B220+CD19+IgD−IgM−) cells derived from p16Ink4a−/−p19Arf−/− mice had Pre-B LBL, suggesting that committed B cells could be the direct cell-of-origin in the absence of p16Ink4a and p19Arf genes which are known as tumor suppressor genes. Lastly, we confirmed that another Myc family gene c-Myc also could induce Pre-B LBL, showing similar histopathology and immunophenotype to the N-Myc-induced pre-B LBL. Collectively, our findings indicate that Myc genes can preferentially transform HSCs into Pre-B LBL and, that p16Ink4a and p19Arf genes can be crucial barriers to block Myc-induced oncogenic stress in more committed cells than HSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3098.
Abstract 3102: Oncogenic PWWP-domain protein WHSC1L1 links the homeobox transcription factor IRX3 in breast cancer
Authors: Liu Gang , YANG Zeng-Quan , Ethier Stephen P. 
Published: February 2011

Abstract
Amplification of the 8p11-12 region has been found in about 10-15% of human breast cancer and may be associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon for identifying candidate oncogenes in breast cancer. We identified Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) as a candidate oncogene based on statistical analysis of copy number increase and over expression. The WHSC1L1 gene encodes a PWWP domain protein that regulates histone methylation marks, and regulates the transcription profile and the differentiated function of cells. To address the question of whether WHSC1L1 possesses transforming properties, we established lentiviral expression constructs containing the WHSC1L1 as well as other 20 candidate genes of 8p11-12 region. MCF10A cells were infected with these lentiviral vectors and assayed for alterations in growth rates, growth factor-independent proliferation, anchorage-independent growth and for three-dimensional morphogenesis assays in Matrigel culture. From these experiments, we found that the WHSC1L1 is the most potently transforming oncogene we tested from the 8p11-12 region. Furthermore, knockdown of this gene in WHSC1L1 amplified breast cancer cells resulted in profound loss of growth and survival potential in these cells. To identify genes that may be regulated in their expression by the WHSC1L1 when it is amplified and over expressed, we performed expression profiling of MCF10A cells, MCF-10AWHSC1L1 cells, and WHSC1L1 amplified SUM-44 breast cancer cells. Analysis of genes altered by over expression of WHSC1L1 in MCF10A-WHSC1L1 cells and in SUM-44 cells resulted in the identification of 184 WHSC1L1 candidate target genes. Among them was the iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family. The regulation of IRX3 gene expression by WHSC1L1 was validated in SUM44 breast cancer cells using WHSC1L1 knock down. IRX3 mRNA was dramatically down-regulated in SUM-44 cells after WHSC1L1 shRNA infection. Intriguingly, in our array CGH study we found that SUM-44 cells also have a gene amplification of IRX3. Thus, our finding indicates that WHSC1L1 is the major driving oncogene in the 8p11-12 amplicon, and provides the first evidence that WHSC1L1 and IRX3 are genetically linked in subset of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3102.
Abstract 3103: Survivin expression is enhanced by the oncoprotein SF2/ASF in non-small cell lung cancer
Authors: Pajares Maria J. , Ezponda Teresa , Agorreta Jackeline , Echeveste Jose I. , Lopez-Picazo Jose M. , Torre Wenceslao , Pio Ruben , Montuenga Luis M. 
Published: February 2011

Abstract
Recent data have shown that the regulation of mRNA metabolism contributes to the genesis of a variety of diseases, including cancer. Modifications in the levels of mRNA processing proteins can elicit global changes in the profile of mRNA expression, affecting a number of cancer-associated genes. The splicing factor SF2/ASF has been described as an oncoprotein with roles both in the establishment and maintenance of a transformed phenotype. The mTOR pathway activation is required for SF2/ASF-mediated transformation, but the specific effectors involved in the SF2/ASF oncogenic potential are not well known. In the present work, we examined the role of SF2/ASF in human non-small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in the SF2/ASF-oncogenic potential. First, we studied the expression of SF2/ASF in human NSCLC by Western blotting and immunocytochemistry. SF2/ASF was overexpressed in most lung cancer cell lines and primary tumors. We next downregulated SF2/ASF expression in NSCLC cells using siRNAs. Inhibition of SF2/ASF induced cell cycle arrest and apoptosis. We found that SF2/ASF inhibition caused a decrease in the main isoform of survivin, an anti-apoptotic protein upregulated in several types of cancer. SF2/ASF specifically bound survivin mRNA, increasing its stability and translation. The translation of survivin mRNA was induced through an mTORC1 pathway-dependent mechanism by the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, we found a strong correlation between the expression of SF2/ASF and survivin in both human NSCLC lung cancer cell lines and primary tumors, supporting the concept that survivin expression levels are controlled by SF2/ASF. In conclusion, we show that SF2/ASF over-expression plays an important role in lung cancer cell survival and provide novel data on the molecular mechanisms of SF2/ASF-mediated oncogenic transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3103.
Abstract 3104: The role of Pim-3 kinase in NF-κB signaling and transformation of pancreatic cancer
Authors: Xu Dapeng , Bednarski Brian , Kim Hongjin , Baldwin Albert , Baines Antonio T. 
Published: February 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 4th most common cause of cancer deaths in the United States. Due to the aggressive nature of this cancer and the lack of biomarkers for early detection, the incidence and mortality rates for PDAC are nearly equivalent. A better understanding of the molecular mechanisms leading to the development of pancreatic cancer remains a major goal for defining appropriate treatment strategies. Past studies have shown that the proto-oncogene Pim-3 kinase is expressed in pancreatic cancer and is able to phosphorylate the pro-apoptotic protein Bad to block Bad-mediated apoptosis in human pancreatic cancer cell lines. With these and other observations implicating Pim kinases as oncogenes and inhibitors of apoptosis, the purpose of our study is to further characterize the functional significance of Pim-3 in PDAC growth as well as identify possible downstream targets. We hypothesize that inhibition of Pim-3 signaling will be an effective approach for antagonizing the aberrant growth of pancreatic cancer. Initially, we confirmed by immunohistochemistry that Pim-3 protein is aberrantly expressed in human pancreatic cancer and pancreatitis tissue and is constitutively expressed in a panel of human pancreatic cancer cell lines. Also, we found that suppression of Pim-3 by shRNAs significantly decreased cell growth and caused a reduction in invasion of pancreatic cancer cells in Matrix-gel. To our knowledge, this is the first time that any of the Pims have been associated with invasion in pancreatic cancer. Most recently, other members of the Pim kinase family have been shown to activate NF-κB in cancer. From our studies, we observed that suppression of Pim-3 upregulated IκBα and decreased phospho-NF-κB p65 (Ser536), suggesting an effect on NF-κB transcription activity. Our results indicate the importance of Pim-3 in various aspects of transformation of pancreatic cancer and how NF-κB may be a potential downstream target of Pim-3 signaling in PDAC. These findings will allow us to critically validate Pim kinases as novel biomarkers and therapeutic targets for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3104.
Abstract 3107: Novel molecular mechanisms of MDM2-induced p21Waf1 degradation
Authors: Xu Hongxia , Zhang Zhuo , Li Mao , Zhang Ruiwen 
Published: February 2011

Abstract
The MDM2 oncogene is overexpressed in many human cancers, and the tumorigenicity of MDM2 has mainly been attributed to the auto-regulatory loop it forms with p53. However, there is increasing evidence that the tumorigenicity of MDM2 is also dependent upon its p53-independent activities. One of the p53-independent functions of MDM2 is its induction of the ubiquitin-independent proteasomal degradation of p21Waf1. The present study was designed to characterize the mechanism(s) by which MDM2 induces p21Waf1 degradation in the p53-independent setting. We determined the regions of MDM2 required for p21Waf1 degradation using pull-down assays and Western blotting, and then examined the mechanisms using limited proteolysis and fluorescence resonance energy transfer (FRET). We demonstrated that the MDM2-p21Waf1 interaction depends on MDM2's central domain, and that nuclear localization of both proteins is necessary for p21Waf1 degradation. Specifically, amino acids 226-250 of MDM2 are required for p21Waf1 binding and degradation, and amino acids 251-260 are necessary for p21Waf1 degradation. The latter region induces a conformation change in p21Waf1, increasing its binding to the C8 subunit of the proteasome, leading to its degradation. When MDM2 lacked either segment (aa 226-250 or aa 251-260), it lost its capacity to promote p21Waf1 degradation and cell cycle progression. In summary, our results demonstrate a novel mechanism by which MDM2 induces the ubiquitin-independent proteasomal degradation of an intact protein. This previously unknown chaperone-like function of MDM2 induces a conformational change in p21Waf1, leading to its increased binding to the C8 subunit of the proteasome to induce its subsequent degradation. It is possible that this mechanism may also be active for other substrates. Thus, the present study provides further evidence supporting the importance of the p53-independent activities of MDM2, confirming the significance of MDM2 as a target for cancer therapy. (Supported by NIH/NCI grants R01 CA 112029 and R01CA121211.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3107.
Abstract 3109: Myc confers aggressive medulloblastoma phenotypes by regulating cell migration and adhesion genes
Authors: Picard Daniel J. , Zhou Limei , Hu Yaqi , Li Meihua , Shih David , Stearns Duncan , Cohn Susan , Hawkins Cynthia E. , Rutka James T. , Taylor Michal D. , Huang Annie 
Published: February 2011

Abstract
Mechanisms by which Myc confers aggressive phenotypes and adverse outcomes in medulloblastoma remain largely unknown. In this study, we demonstrate using 2 medulloblastoma cell line models that high Myc expression increases cell migration/invasion and induces metastatic orthotopic tumors which recapitulate the aggressive histology of primary anaplastic medulloblastoma. Using ChIP-chip and expression analysis on Myc transformed medulloblastoma cell lines, we identified a subset of cell migration and adhesion genes as direct Myc repressed transcriptional targets. These include ING4, PVRL3, PPAP2B and Tsp-1/THBS1, a potent tumor suppressor not previously implicated in medulloblastoma. Tsp-1 expression in medulloblastoma cell lines and primary tumors were consistently and significantly diminished in the presence of high Myc (n=101, p=0.032). Using ChIP and reporter assays we confirmed Myc and Max co-localization to a basal Tsp-1 promoter and decreased Tsp-1 transcription in the presence of Myc. Our analyses also revealed that JPO2, a Myc interacting protein linked to metastatic medulloblastoma, directly binds the Tsp-1 promoter and augments Myc-mediated Tsp-1 repression. Interestingly, we observed that stable Tsp-1 expression significantly diminished soft agar growth and drastically decreased cell invasion/migration in high-Myc expressing medulloblastoma cell lines without effects on cellular proliferation. Our collective findings highlight a novel and important role for Tsp-1 in Myc- induced metastatic medulloblastoma phenotypes and suggest Tsp-1 agonists may represent attractive, therapeutics for primary metastatic medulloblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3109.
Abstract 3112: TIS21BTG2/PC3 enhances down-regulation of c-Myc expression during all-trans-retinoic acid-induced differentiation of acute promyelocytic leukemia cells
Authors: Imran Muhammad , Park Tae Jun , Lim In Kyoung 
Published: February 2011

Abstract
c-Myc is a transcription factor that promotes cell growth and proliferation. Deregulated c-myc can induce aberrant proliferation, loss of terminal differentiation and oncogenesis. On the other hand, the 12-O-tetradecanoyl phorbol-13-acetate inducible sequence 21 (TIS21), ortholog of human B-cell translocation gene-2 (BTG2) is an antiproliferative tumor suppressor gene, working as a pan-cell cycle regulator. In this study we have evaluated the effects of all-trans retinoic acid (ATRA) and TIS21BTG2/PC3 on the expression c-Myc in HL-60 promyelocytic leukemia cells, harboring amplified c-myc. We observed that ATRA induced granulocytic differentiation of HL-60 cells as monitored by the expressions of CD11b, CD14, CD38 and microscopic examination of the cells. ATRA treatment led to decrease in cells proliferation accompanied by down-regulation of cyclin D1, cyclin E and cyclin A while up-regulation of p21WAF1 and p27KIP1 and hence G1 phase arrest. Expression of c-Myc was significantly down-regulated during all-trans-retinoic acid induced differentiation, while BTG2TIS21/PC3 was up-regulated (∼2.5 folds). Employing adenovirus carrying TIS21 gene, we observed the slight down regulation of c-Myc expression; TIS21 however, enhanced ATRA-induced differentiation of HL-60 cells to granulocytes and significantly increased down-regulation of c-Myc expression at protein level but mRNA level didn't change. Proteosomal inhibition with MG132 didn't attenuate c-Myc protein levels indicating that ubiquitination/proteosome-mediated proteolysis is not involved in TIS21BTG2/PC3 mediated down-regulation of c-Myc. Inhibition of PI3K/Akt/mTOR pathway with LY294002 however, suggested the possible involvement of TIS21BTG2/PC at least in part through PI3K/Akt/mTOR pathway in regulating c-Myc expression. The present results suggest the modulating effect of TIS21BTG2/PC3 on c-Myc expression in a promyelocytic leukemia cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3112.
Abstract 3113: Loss of TLE1 tumor suppressor accelerates myeloid leukemia development in cooperation with N-Myc
Authors: Ramasamy Selvi , Chen Xi , Wang Jianfeng , Ding Daching , Sweetser David A. 
Published: February 2011

Abstract
Transducin-like enhancer of split-1 (TLE1) is a novel tumor suppressor gene that is deleted or methylated in subgroups of acute myeloid leukemia (AML) and other hematological malignancies. TLE1 belongs to a family of Gro/TLE proteins that function as corepressors that can bind and potentially inhibit numerous transcription factors known to be involved in development and carcinogenesis including myc, beta-catenin, NF-kB, and TGF-B. In Drosophila Groucho is recognized as a master regulatory gene in development. Our studies and those from other groups have shown that over-expression of TLE1 in leukemia cells slows cell cycle progression, colony formation and tumor growth in xenografts, while silencing results in increased cell proliferation. To further evaluate the role of TLE1 in development and oncogenesis we have knocked out TLE1 in mice. These mice are viable and do not spontaneously develop malignancies in the absence of additional cooperating oncogenes. In Drosophila the TLE homologue Groucho binds and represses Drosophila Myc expression of target genes. N-Myc is important for hematopoietic stem cell proliferation, survival and differentiation and is over-expressed in most AML samples. We postulated that TLE 1 might be an important regulator of N-Myc activity in leukemia and the loss of TLE may accelerate the leukemia development in cooperation with N-Myc. We demonstrate here that the loss of Tle1 cooperates with N-Myc to dramatically increase the serial replating and proliferation of hematopoietic progenitor cells from fetal livers. Mice transplanted with N-Myc transduced hematopoietic cells from the fetal liver of Tle1 knockout mice developed leukemia with a much shorter latency as compared with fetal liver cells from wild type mice. We are currently investigating the mechanisms of this cooperation. This is the first demonstration that Tle1 is a potent modulator of Myc induced tumorigenesis and may have implications in a broader spectrum of malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3113.
Abstract 3114: MLL2 overexpression and incomplete proteolytic processing in human cell lines from invasive breast and colon cancers
Authors: Natarajan Thanemozhi G. , Kallakury Bhaskar V. , Sheehan Christine , Bartlett Margaret B. , Ganesan Natarajan , Preet Anju , Ross Jeffrey , FitzGerald Kevin T. 
Published: February 2011

Abstract
Background: MLL2 is an epigenetic regulator in mammalian cells and mediates histone 3 lysine 4 tri-methylation (H3K4me3) at specific gene loci, through formation of a multiprotein complex. MLL2 shares a high degree of structural similarity with MLL1, which frequently undergoes translocations resulting in leukemogenic fusion oncoproteins. Despite the structural similarity with MLL1, MLL2 is not involved in leukemias. Earlier we reported aberrant MLL2 expression in human breast and colonic tumor tissues compared to normal tissues. In continuation with the above study, we now present the results of MLL2 investigation in cell lines from human breast and colon cancers.
Methods: Established cell lines from human mammary and colonic tissues were cultured under optimal conditions. Cells were processed for nuclear and cytoplasmic fractionation as well as DNA and total RNA extraction. Nuclear and cytoplasmic extracts were separated on polyacrylamide gels and immunoblotted for MLL2. The RNA extracts were used to determine MLL2 transcript levels by one-step reverse transcriptase-PCR using appropriate primers. The DNA extracts were used to amplify MLL2 specific sequences using appropriate primers, followed by sequencing reaction.
Result: Examination of cell lines revealed 2-3 fold increase in MLL2 transcript levels in the highly invasive tumor cell lines of both breast and colon. Expression of MLL2 at protein level was consistent with the transcript levels, indicating MLL2 overexpression as the cause of increased protein levels in the tumor cells. Additionally, we also observed incomplete proteolytic processing of MLL2 in the highly invasive cell lines from either tissue types, compared to the corresponding non-tumor/less invasive tumor cell lines. Interestingly, the unprocessed full length MLL2 was significantly abundant in the nuclear compartments of the highly invasive tumor cell lines. Analysis of the coding sequences for the putative cleavage site did not reveal any alterations.
Conclusion: We conclude that MLL2 expression and proteolytic processing are both deregulated in breast and colon cancers. This deregulation may be associated with mammary and colonic tumor growth/progression. Given the epigenetic regulatory role, further investigation is required to study MLL2 involvement in tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3114.