bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA03: Role of MYC in germinal-center development and in lymphomagenesis
Authors: Dalla-Favera Riccardo 
Published: October 2015

Abstract
Germinal centers (GCs) are transient structures that form in second¬ary lymphoid organs where B cells are selected on the basis of their ability to produce high-affinity antibodies. B cells in the GCs are also the cells of origin for most B cell lymphomas, including Burkitt Lymphoma carrying chromosomal translocations involving c-Myc. After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. We have shown that the GC reaction requires a biphasic regulation of expression of c-Myc that involves: 1) its transient induction during early GC commitment; 2) its repression by Bcl-6 in highly proliferating DZ B cells; 3) its re-induction in B cells selected for reentry into the DZ. Elimination of c-MYC expression during GC formation results in GC absence, while its inhibition in formed GCs leads to GC collapse. Thus c-Myc has essential roles in early induction of GCs and in their maintenance, by eliminating the LZ-to DZ recirculation. These results suggest an unusual, independent of cell proliferation role of c-Myc in GC development and has implications for the role of c-Myc in lymphomagenesis. By overriding the physiological control of c-Myc expression at critical checkpoints in the GC reaction (entry into the GC and reentry into the DZ), translocations involving immunoglobu¬lin loci and c-MYC may allow B cells to bypass affinity-based selection signals and impose a continuous reentry phenotype that, by perturb¬ing normal GC dynamics, may contribute to lymphomagenesis.
Note: This abstract was not presented at the conference.
Citation Format: Riccardo Dalla-Favera. Role of MYC in germinal-center development and in lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA03.
Abstract IA04: Neuroblastoma as a paradigm of MYC(N) driven cancers
Authors: Maris John M. 
Published: October 2015

Abstract
Neuroblastoma is an enigmatic childhood cancer with phenotypes ranging from spontaneous regression of seemingly advanced disease to relentless metastatic progression. MYCN amplification was defined as a powerful predictor of metastatic potential and acquisition of therapy resistance in the 1980's, and arguably was the first genomic biomarker utilized in routine clinical practice to stratify therapeutic intensity. While there have been incremental improvements in cure rates over the last three decades, these have come at the cost of a highly complex and intensive chemoradiotherapeutic regimen that leaves survivors with significant long-term morbidity. Here we will discuss our ongoing efforts to define the genetic basis of neuroblastoma, and recent insight into how heritable DNA variation influences neuroblastoma susceptibility and clinical phenotypes, including MYCN amplification. We will also discuss the major oncogenic drivers of high-risk neuroblastoma beyond MYCN, including recent insights into the role of MYC in the MYCN-non-amplified high-risk cases, as well as the major role of the ALK oncogene, often in cooperation with MYCN. Finally, we will discuss recent efforts to leverage this information therapeutically, with a focus on how therapeutically targetable oncogenic pathways evolve under the selective pressure of chemoradiotherapy. Finally, we will discuss nascent efforts to deliver on the holy grail of neuroblastoma translational research—targeting the MYCN oncoprotein itself, discussing opportunities and challenges.
Citation Format: John M. Maris. Neuroblastoma as a paradigm of MYC(N) driven cancers. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA04.
Abstract IA05: Targeting MYC-mediated cancer metabolism
Authors: Dang Chi Van 
Published: October 2015

Abstract
Myc, as a transcription factor capable of amplifying gene expression, frequently activates genes involved in cell metabolism to support cell growth and proliferation. Because many metabolic genes are ambiently expressed, it is not surprising in retrospect, that many metabolic genes are targets for Myc-mediated gene expression amplification. Collectively, Myc drives the expression of genes that are involved in glucose uptake, glycolysis, amino acid uptake - particularly glutamine- and catabolism, supporting increased protein synthesis required for a growing cell. In this regard, Myc stimulates many genes involved in nucleotide synthesis, ribosome biogenesis and translation. Furthermore, Myc can stimulate mitochondrial biogenesis and lipogenesis. When Myc is ectopically expressed in oncogenic settings where checkpoints are lost, MYC-transformed cells are constitutively driven to undergo ribosome biogenesis and growth, rendering them addicted to nutrients such as glucose or glutamine. Hence, targeting enzymes that are involved in glycolysis and/or glutaminolysis provides a strategy to treat MYC-driven cancers. We provide proof-of-concept that targeting glutaminolysis in GEMM or xenograft models is feasible and therefore provide a foundation for further studies.
Citation Format: Chi Van Dang. Targeting MYC-mediated cancer metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA05.
Abstract IA07: Metabolic reprogramming by MYC: Lessons learned from adenovirus
Authors: Christofk Heather 
Published: October 2015

Abstract
Viruses are powerful tools to study cancer metabolism. They trigger major metabolic changes in host cells to meet the bioenergetic and biosynthetic demands of virus infection - changes similar to the enhanced glycolysis and anabolic metabolism widely observed in cancer cells. However, unlike cancer cells, viruses undergo intense selection for efficiency, and rapidly and robustly reprogram host cell metabolism through activation of specific key flux-altering nodes, rather than whole metabolic pathway gene sets. We recently reported that adenovirus infection increases host cell anabolic glucose metabolism via MYC activation of specific metabolic target genes, only a subset of those turned on by MYC in many cancers. We are now investigating how adenovirus-induced MYC activation leads to selective transcription of target genes. Additionally, we have generated a list of the specific metabolic genes altered by adenovirus infection and are examining their role in anabolic metabolism, virus replication, and cancer proliferation. Because viruses are so efficient at reprogramming host cell metabolism towards increased anabolism, they represent a powerful tool to identify the most important MYC-induced metabolic enzymes for anabolic metabolism, and potentially the most promising cancer metabolism drug targets.
Citation Format: Heather Christofk. Metabolic reprogramming by MYC: Lessons learned from adenovirus. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA07.
Abstract IA10: Post-translational regulation of MYC's oncogenic activity
Authors: Sears Rosalie , Farrell Amy , Wang Xiaoyan , Liang Juan , Janghorban Mahnaz , Su Yulong , Allen-Petersen Brittany , Ohlemeyer Michael , Goutham Narla 
Published: October 2015

Abstract
In response to growth stimulatory signals in normal cells or in transformed cells with constitutive signaling, the c-Myc oncoprotein is post-translationally stabilized through enhanced phosphorylation at the conserved Serine 62 residue. In addition to increasing c-Myc stability, phosphorylation at Serine 62 (pS62-Myc), in conjunction with Proline 63 isomerization mediated by the Pin1 Proline Isomerase, also increases the rate of recruitment of newly synthesized c-Myc to its target genes involved in pro-proliferative phenotypes, enhancing their expression. In normal cells, phosphorylation of S62 primes phosphorylation at a second conserved residue, Threonine 58 (pT58), which then enhance c-Myc degradation by facilitating a second Pin1-mediated isomerization event, which promotes Protein Phosphatase 2A (PP2A-B56α)-mediated dephosphorylation of Serine 62 and recruits the E3 ubiquitin ligase, SCFFbw7. In cancer cell lines as well as patient tumor samples pS62-Myc is elevated relative to non-transformed cell lines or adjacent normal tissue. In order to study the role of pS62-Myc in vivo, we created c-Myc knock-in mice that express either Myc wild-type (WT) or the MycT58A or MycS62A phosphorylation mutant from the ROSA26 locus in response to Cre-recombinase. Analysis of these mice revealed increased tumorigenic potential of MycT58A, which has constitutive S62 phosphorylation as it is resistant to PP2A-mediated S62 dephosphorylation. Together, this research has revealed an important role for S62 phosphorylation and Pin1-mediated isomerization in the tumorigenic activity of c-Myc, which presents new strategies to target c-Myc by inhibiting these post-translational activation steps. Thus, we are currently testing the therapeutic efficacy of PP2A activation and Pin1 inhibition in mouse models of c-Myc-driven tumorigenesis. To create physiologically relevant c-Myc-driven tumor models that engage post-translational activation of c-Myc, we have crossed our ROSA-LSL-MycWT mice with mice carrying organ-relevant oncogenic signaling transgenes. Thus far, we have generated mouse models of Her2+ and Triple Negative breast cancer, and pancreatic cancer. We have demonstrated dramatic tumor growth inhibition with a novel, orally available small molecule PP2A activator drug in these mouse models.
Citation Format: Rosalie Sears, Amy Farrell, Xiaoyan Wang, Juan Liang, Mahnaz Janghorban, Yulong Su, Brittany Allen-Petersen, Michael Ohlemeyer, Narla Goutham. Post-translational regulation of MYC's oncogenic activity. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA10.
Abstract IA24: MYC in germinal center B cell physiology and pathology
Authors: Calado Dinis Pedro 
Published: October 2015

Abstract
Germinal centers (GC)s are sites of intense B-cell proliferation, central for T-cell dependent antibody responses. Although much is known of GC B-cell physiology, the mechanisms of cellular proliferation have remained elusive. Specifically, the role of MYC, a key cell cycle regulator, in GC B-cell proliferation has been questioned. We have identified MYC positive B-cell subpopulations in both immature and mature GCs, and shown through genetic ablation of Myc at these stages that they play indispensable roles in GC formation and maintenance, respectively. The identification of functionally critical MYC-expressing GC B-cell subsets has important implications for B-cell lymphomagenesis, which mostly originates from GC cells and frequently involves MYC deregulation through chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the MYC positive GC subpopulations may represent B-cells with a particularly high risk for malignant transformation.
Citation Format: Dinis Pedro Calado. MYC in germinal center B cell physiology and pathology. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA24.
Abstract PR01: Long noncoding RNA PVT1 potentiates MYC in human cancers with 8q24 gain
Authors: Tseng Yuen-Yi , Bagchi Anindya 
Published: October 2015

Abstract
Copy number gain of the 8q24.21 chromosomal region have been a prominent mutation in many human cancers and are associated with poor prognosis. The well-characterized MYC oncogene, which resides in the 8q24.21 region, has been, conventionally, the attractive candidate driving these cancers. However, MYC is often co-gained with an adjacent ”gene desert” region. This “gene desert” often encompasses the long non-coding RNA gene PVT1, the CCDC26 gene candidate, and the GSDMC gene. Whether low copy number gain of one or more of these genes drives neoplasia is not known. We used chromosome engineering in mice to develop strains containing an extra copy of 1) Myc, 2) Pvt1, Ccdc26, Gsdmc, and 3) Myc, Pvt1, Ccdc26, Gsdmc. When rat Neu was introduced into these three strains to test for changes in latency and penetrance in mammary tumor development, only the mice with an extra copy of Myc, Pvt1, Ccdc26, Gsdmc, (but not those with an extra copy of Myc or Pvt1,Ccdc26,Gsdmc), developed adenocarcinomas with reduced latency, suggesting that while an additional copy of the Myc gene failed to measurably advance cancer, it may co-operate with Pvt1, Ccdc26 or Gsdmc to promote cancer. Si-RNA mediated knockdown of Pvt1/PVT1 reduced the proliferation rates in the mouse mammary tumors, as well as in two human breast cell lines with 8q24 amplification (SK-BR-3 and MDA-MB-231). Silencing of PVT1 markedly decreased MYC protein levels, while no effect was seen in MYC transcript levels, suggesting a PVT1-dependence of MYC protein even in high MYC- amplification cancer cells. Analysis of the TCGA and Progenetix databases suggested that 18% of 45,922 human tumors queried harbor MYC copy number increases, and in &gt;99% of MYC-copy-increase cancers, copy number of PVT1 was co-increased .Tissue microarray analysis using in situ hybridization for PVT1 and immunohistochemistry for MYC revealed that PVT1 RNA and MYC protein expression correlated in primary human tumors. These data together suggested that PVT1 can potentiate MYC in human cancer. CRISPR mediated deletion of PVT1 in colorectal cancer cell line HCT116 either partially or fully ablated tumor formation in xenografts and significantly reduced MYC protein levels by ~50%. We propose that the dependence of high MYC protein levels on PVT1 lncRNA provides a much-needed therapeutic target against MYC protein, which has been refractory to small molecule inhibition.
Citation Format: Yuen-Yi Tseng, Anindya Bagchi. Long noncoding RNA PVT1 potentiates MYC in human cancers with 8q24 gain. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR01.
Abstract PR05: Targeting of CDK7 inhibits super-enhancer-associated oncogenic programs in MYCN-amplified tumor cells
Authors: Chipumuro Edmond , Marco Eugenio , Christensen Camilla L. , Kwiatkowski Nicholas , Zhang Tinghu , Hatheway Clark M. , Abraham Brian J. , Sharma Bandana , Yeung Caleb , Altabef Abigail , Perez-Atayde Antonio , Wong Kwok-Kin , Yuan Guo-Cheng , Gray Nathanael S. , Young Richard A. , George Rani E. 
Published: October 2015

Abstract
The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a novel covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, would be useful therapy for cancers that are driven by MYC or its family members.
Citation Format: Edmond Chipumuro, Eugenio Marco, Camilla L. Christensen, Nicholas Kwiatkowski, Tinghu Zhang, Clark M. Hatheway, Brian J. Abraham, Bandana Sharma, Caleb Yeung, Abigail Altabef, Antonio Perez-Atayde, Kwok-Kin Wong, Guo-Cheng Yuan, Nathanael S. Gray, Richard A. Young, Rani E. George. Targeting of CDK7 inhibits super-enhancer-associated oncogenic programs in MYCN-amplified tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR05.
Abstract PR10: Preclinical validation of Myc inhibition by a new generation of Omomyc-based cell penetrating peptides
Authors: Beaulieu Marie-eve , Whitfield Jonathan , Massó-Vallés Daniel , Jauset Toni , Serrano Erika , Montagne Martin , Maltais Loika , Tremblay Cynthia , Lavigne Pierre , Soucek Laura 
Published: October 2015

Abstract
Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which proved to be the most effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a proof of principle. Here we report the exciting finding that Omomyc-based Cell Penetrating Peptides (CPPs) are a novel, state-of-the-art method for directly utilizing Omomyc itself (and similar peptides) to treat tumors in the lung and brain, where the peptides biodistribute after intranasal administration. We provide a comprehensive preclinical validation of this innovative therapeutic approach for pharmacological inhibition of Myc in cancer cell lines of different origin and genetic make-up, as well as in a mouse model of Non-Small-Cell Lung Cancer (NSCLC), where the Omomyc-CPPs, like their transgenic counterpart before, display a dramatic therapeutic impact.
Citation Format: Marie-eve Beaulieu, Jonathan Whitfield, Daniel Massó-Vallés, Toni Jauset, Erika Serrano, Martin Montagne, Loika Maltais, Cynthia Tremblay, Pierre Lavigne, Laura Soucek. Preclinical validation of Myc inhibition by a new generation of Omomyc-based cell penetrating peptides. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR10.
Abstract PR15: ERK2 binds to MYC promoter and induces MYC expression
Authors: Quintanilla Andrea , Rodriguez Javier , Garcia-Gutierrez Lucía , Lorena Agudo , Crespo Piero , León. Javier 
Published: October 2015

Abstract
It has been known since 30 years ago that serum and growth factors induce a dramatic upregulation of MYC expression in quiescent cells, but the molecular mechanism for this effect is unknown. It has been reported that ERK can bind to DNA and modify gene expression (Hu et al., Cell, 2009). We have investigated the possibility that ERK directly upregulates MYC at the transcriptional level. We have found that: (i) Bioinformatic analyses reveal the presence of ERK binding sites (ERK boxes) conserved in human, mice and rat MYC promoters, located at -0.3 kbp, -1 kbp and -1.7 kbp from the transcription star site; (ii) ERK binds to these ERK boxes by chromatin immunoprecipitation (ChIP) in rat, mouse and human cells upon ERK stimulation, attained either by serum, induction of a N-Ras oncogene or by transfection of a nuclear tethered ERK2; (iii) ERK2 binding correlates with the upregulation of MYC mRNA and protein; (iv) ERK2 activates a luciferase reporter containing a conserved ERK box of the human MYC gene, but not a reporter with the mutated ERK box; (v) ERK2 binds to Cdk9 (the kinase component of pTEFb) in the nucleus as assessed by co-immunoprecipitation and in situ Proximity Ligase Assay (PLA); (vi) the ChIP signal on human MYC promoter detected with anti-ERK2 coincides with that observed with anti-Cdk9 antibodies; and (vii) siRNA-mediated knock-down of Cdk9 impairs MYC up-regulation by ERK2. In the data obtainied so far, we hypothesize that the induction of MYC in response to serum or growth factors might follow this mechanism: growth factors &gt; Ras activation &gt; ERK translocation to nuclei &gt; binding to MYC promoter &gt; recruitment or hyperactivation of pTEFb factor &gt; MYC transcription.
Citation Format: Andrea Quintanilla, Javier Rodriguez, Lucía Garcia-Gutierrez, Agudo Lorena, Piero Crespo, Javier León. ERK2 binds to MYC promoter and induces MYC expression. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR15.
Coexistent Types of Atrioventricular Nodal Re-Entrant Tachycardia
Authors: Katritsis Demosthenes G. , Marine Joseph E. , Latchamsetty Rakesh , Zografos Theodoros , Tanawuttiwat Tanyanan , Sheldon Seth H. , Buxton Alfred E. , Calkins Hugh , Morady Fred , Josephson Mark E. 
Published: October 2015

Background—
There is evidence that atypical fast–slow and typical atrioventricular nodal re-entrant tachycardia (AVNRT) do not use the same limb for fast conduction, but no data exist on patients who have presented with both typical and atypical forms of this tachycardia. We compared conduction intervals during typical and atypical AVNRT that occurred in the same patient.

Methods and Results—

In 20 of 1299 patients with AVNRT, both typical and atypical AVNRT were induced at electrophysiology study by pacing maneuvers and autonomic stimulation or occurred spontaneously. The mean age of the patients was 47.6±10.9 years (range, 32–75 years), and 11 patients (55%) were women. Tachycardia cycle lengths were 368.0±43.1 and 365.8±41.1 ms, and earliest retrograde activation was recorded at the coronary sinus ostium in 60% and 65% of patients with typical and atypical AVNRT, respectively. Thirteen patients (65%) displayed atypical AVNRT with fast–slow characteristics. By comparing conduction intervals during slow–fast and fast–slow AVNRT in the same patient, fast pathway conduction times during the 2 types of AVNRT were calculated. The mean difference between retrograde fast pathway conduction during slow–fast AVNRT and anterograde fast pathway conduction during fast–slow AVNRT was 41.8±39.7 ms and was significantly different when compared with the estimated between-measurement error (
P
=0.0055).

Conclusions—
Our data provide further evidence that typical slow–fast and atypical fast–slow AVNRT use different anatomic pathways for fast conduction.