bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: Role of ribosomal protein, Rpl22 in regulating leukemic transformation.
Authors: Patel Nehal Solanki , Greenberg Noa , Peri Suraj , Rao Shuyun , Rhodes Michele , Wiest David 
Published: August 2015

Abstract
Inactivation of ribosomal proteins (RP) is known to cause diseases called ribosomopathies, which are often associated with abnormal hematopoiesis and an increased risk for development of leukemia. Our laboratory has recently reported an important link between inactivation of one such ribosomal protein, Rpl22, and poor survival in T cell acute lymphoblastic leukemia (T-ALL) patients. Preliminary bioinformatic analysis shows that RPL22 is lost in ~10% of pediatric T-ALL patients, who exhibit a more aggressive disease course. Deletion of the RPL22 locus is also enriched in the early T-cell precursor (ETP-ALL) subset of T-ALL patients, which exhibit a more aggressive disease course. Thus, RPL22 loss appears to be a marker for poor outcome in pediatric T-ALL patients. While RP inactivation has previously been linked to increased cancer risk, the mechanistic basis for this linkage remained unclear. We have recently demonstrated that inactivation of Rpl22 promotes leukemic transformation by activating NF-kB and inducing the stem cell gene, LIN28B. Nevertheless, the molecular link between Rpl22 inactivation and the induction of NF-kB activity remained unclear. We have now determined that inactivation of Rpl22 activates NF-kB signaling by exacerbating ER stress responses. Indeed, Rpl22 loss results in hyperactivation of the PERK-EIF2α-ATF4 stress pathway, which is known to activate NF-kB. We have demonstrated that knockdown of PERK using shRNA abrogates the activation of NF-kB in Rpl22 mutant cells and returns Lin28B expression levels to baseline. This reduction in Lin28B eliminates the predisposition to transformation exhibited by Rpl22 mutant cells, as evidenced by decreased formation of colonies in soft agar. Taken together, these data suggest that RPL22 inactivation may serve as a negative prognostic indicator in T-ALL and that pharmacologic targeting of ER stress pathways may represent a novel therapeutic alternative in this molecularly-defined subclass of T-ALL.
Citation Format: Nehal Solanki Patel, Noa Greenberg, Suraj Peri, Shuyun Rao, Michele Rhodes, David Wiest. Role of ribosomal protein, Rpl22 in regulating leukemic transformation. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B26.
Abstract B46: VLA-4 targeted nanoparticles carrying a novel anti-Myc prodrug prolongs survival in a mouse model of multiple myeloma.
Authors: Gupta Deepti Sood , Pan Dipanjan , Hu Grace , Senpan Anagana , Yang Xiaoxiao , Prochownik Edward V. , Lanza Gregory M. , Tomasson Michael H. 
Published: August 2015

Abstract
The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We determined the efficacy of lipase labile MYC-MAX inhibitor prodrug (MI1-PD) loaded nanoparticles targeted via integrin {alpha 4 beta1 α4β1) or Very Late Antigen-1 (VLA-4)} in myeloma mice. We hypothesized that NPs containing specific targeting to myeloma cells, would enhance the therapeutic efficacy of MI1-PD containing NPs. The antiproliferative activity of intergin VLA-4-Targeted MI-1PD NPs (iTM-NPs) was determined in mouse cell line (5TGM1) in vitro and its effect on the survival in C57Bl/KaLwRij-5TGM1 murine model of myeloma in vivo. iTM-NPs (approximately 20 nm in diameter, 5% w/w MI1-PD loading) under in vitro conditions exhibited inhibition of cell growth compared to the controls. Also, C57Bl/KaLwRij-5TGM1 mice that received intravenous injection of iTM-NPs demonstrated greater survival rate over the controls. These results demonstrate the feasibility of using VLA-4 targeted nanotherapy approach to improve the availability of anti-Myc small molecule inhibitors for multiple myeloma and other cancers.
Citation Format: Deepti Sood Gupta, Dipanjan Pan, Grace Hu, Anagana Senpan, Xiaoxiao Yang, Edward V. Prochownik, Gregory M. Lanza, Michael H. Tomasson. VLA-4 targeted nanoparticles carrying a novel anti-Myc prodrug prolongs survival in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B46.
Abstract IA08: The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets.
Authors: Burger Jan A. 
Published: August 2015

Abstract
The tissue microenvironment plays an important role of in the pathogenesis of chronic lymphocytic leukemia (CLL), delivering signals that promote the clonal expansion of the malignant B cells, as well as drug resistance. The complex cross talk between neoplastic B cells and the microenvironment, for example in secondary lymphoid organs, has been increasingly well characterized, and several cellular and molecular key players have emerged. Important cells in the CLL microenvironment are monocyte-derived nurselike cells (NLC), mesenchymal stromal cells (MSC), and T cells, which engage in a dialogue with the neoplastic CLL cells, often via specific receptor-ligand pairs. Engagement of CLL surface receptors by ligands in the tissue microenvironment, for example activation of B cell receptor (BCR) signaling, triggering of TNF family members (i.e. BAFF, APRIL), and activation of chemokine receptors and adhesion molecules result in the activation of signaling cascades that support the maintenance and expansion of the CLL clone. BCR signaling plays a particularly important pathogenic role in CLL, based on structural restrictions of the BCR, and signs of BCR-dependent survival and growth of the malignant B cells. Ligand-independent (“autonomous”) and ligand-dependent BCR signaling have been characterized, the latter triggered by (auto-) antigens present in the tissue microenvironment. Based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases (BTK, PI3Kδ), which currently are changing treatment paradigms in CLL. Clinical and translational aspects of these new targeted therapeutics will be discussed, along with an outlook into future therapeutic strategies.
Citation Format: Jan A. Burger. The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA08.
Abstract IA19: The evolutionary landscape of chronic lymphocytic leukemia.
Authors: Wu Catherine J. 
Published: August 2015

Abstract
Clonal evolution is a key feature of cancer progression and relapse. Recent studies across cancers have demonstrated the extensive degree of intratumoral heterogeneity present within individual cancers. We hypothesized that evolutionary dynamics contribute to the variations in disease tempo and response to therapy that are highly characteristic of chronic lymphocytic leukemia (CLL). We have recently investigated this phenomenon by developing a pipeline that estimates the fraction of cancer cells harboring each somatic mutation within a tumor through integration of whole-exome sequence (WES) and local copy number data (Landau et al., Cell 2013). By applying this analysis approach to 149 CLL cases, we discovered earlier and later cancer drivers, uncovered patterns of clonal evolution in CLL and linked the presence of subclones harboring driver mutations with adverse clinical outcome. Thus, our study, generated from a heterogeneous sample cohort, strongly supports the concept that CLL clonal evolution arises from mass extinction and therapeutic bottlenecks which lead to the emergence of highly fit (and treatment resistant) subclones.
We further hypothesize that epigenetic heterogeneity also shapes CLL clonal evolution through interrelation with genetic heterogeneity. Indeed, in recent work, we have uncovered stochastic methylation disorder as the primary cause of methylation changes in CLL and cancer in general, and that this phenomena impacts gene transcription, genetic evolution and clinical outcome. Ongoing studies focus on establishing a framework for understanding the stepwise transformation of B cells, and elucidating the role of the dynamic evolutionary landscape of CLL on its diagnosis, prognosis and treatment.
Citation Format: Catherine J. Wu. The evolutionary landscape of chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA19.
Abstract IA21: AML genomics: An update.
Authors: Mardis Elaine R. 
Published: August 2015

Abstract
Our fundamental understanding of the genomic landscape of acute myeloid leukemia (AML) has significantly improved due to large-scale genomic characterization of AML genomes, transcriptomes and methylomes. Retrospective analyses of primary and relapse disease genomes has also illustrated the changes in heterogeneity that occur during progression, and studies of mouse xenografts of AML have illustrated the biological competition among subclones to seed progressive disease. I will discuss next steps in our clinical sequencing of AML, aimed at beginning to apply our fundamental knowledge about the disease to the cancer care setting. Various technical challenges will be highlighted as well as discussing the overall framework for beginning to understand the data we will generate.
Citation Format: Elaine R. Mardis. AML genomics: An update. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA21.
Abstract IA24: Regulation of acute leukemia initiation and progression by long noncoding RNAs.
Authors: Aifantis Iannis 
Published: August 2015

Abstract
Recent efforts to functionally annotate the human genome have revealed that up to 70% of our DNA is transcriptionally active. Since a very small portion of our genome encodes proteins many have hypothesized that a portion of this pervasive transcription results in production of non-coding RNA. By generating high depth RNA-Seq datasets integrated with chromatin features, several labs have revealed the presence of many thousands of previously un-annotated long non-coding RNAs (lncRNA), which are dynamically expressed in response to various stimuli in diverse cellular contexts. Despite these compelling advances, the vast majority of putative lncRNAs have not been proven to be functionally important, although a small portion have clearly been shown to play key regulatory roles. Most importantly, very little is known on the biological role of lncRNAs for human disease and specifically cancer. We provide here, using a combination of deep transcriptome sequencing, high-resolution transcription factor occupancy mapping and chromosome conformation capture data, the first comprehensive identification and characterization of lncRNA expression and function in T-cell acute lymphoblastic leukemia, an aggressive hematologic malignancy affecting both children and adults, driven by oncogenic NOTCH1 mutations and transcriptional activation. Moreover, we provide the first map of oncogene (NOTCH1)-targeted lncRNAs in this disease and identify an individual lncRNA (called LUNAR1) that appears to be essential for tumor growth as it controls cytokine (IGF1) signaling. Indeed, we were able to show that the LUNAR1 locus loops on a novel IGF1R enhancer controlling the expression of this important cytokine receptor. These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer, b) more efficient methods for large-scale inference and validation of lncRNA function are needed to fully understand their biological significance and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target. These points will be addressed in this presentation.
Citation Format: Iannis Aifantis. Regulation of acute leukemia initiation and progression by long noncoding RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA24.
Abstract IA33: Regulation of self-renewal in cancer stem cells.
Authors: Falzacappa Maria Vittoria Verga , Insinga Alessandra , Pelicci Pier Giuseppe 
Published: August 2015

Abstract
We showed that extended self-renewal of leukemia stem-cells (LSCs) is the consequence of the constitutive activation of the cell-cycle inhibitor p21. The pool of LSCs is markedly reduced in p21-/- APLs, and the residual LSCs hyperproliferate and accumulate massive DNA-damage (DD). Notably, p21 is indispensable to maintain the pool of LSCs in PML-RAR leukaemias (PML-RAR – p21-/- leukaemias are not transplantable in syngenic mice). It is not known whether p21 extends the self-renewal of LSCs by activating DD repair, restricting the cell-cycle or regulating their survival. Preliminary results from our lab showed that p21-/- APLs re-acquire the ability to initiate leukemogenesis when transplanted into immunodeficient mice (RAG) or syngeneic mice after γ-irradiation. In these conditions, the growing leukemias are indistinguishable from primary WT APLs and can be re-transplanted into immunodeficient, but not syngeneic mice, suggesting that expansion of p21-/- LSCs is controlled by the host immune-system. Further experiments suggested that p21-/- LSCs are cleared by T-cells since p21-/- APLs: i) initiate leukemias when transplanted into RAG1-/- mice (which lack B, T and NKT cells), but not in JHT mice (lacking only B-cells), and ii) do not grow in NOD/SCID mice when the recipients are injected with a T cell population primed with p21-/- blasts (e.g. obtained from the spleen of WT mice injected with p21-/- APLs), but not with non-primed T cells or T cells primed with WT blasts. T-cells primed with p21-/- blasts are also able to suppress the in vivo growth of wt APLs, but not of T-ALLs. We hypothesize that the immune-surveillance contributes to the elimination of DNA-damaged SCs, and that DNA-damaged LSCs have developed evasion strategies based on p21 activation.
Citation Format: Maria Vittoria Verga Falzacappa, Alessandra Insinga, Pier Giuseppe Pelicci. Regulation of self-renewal in cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA33.
Abstract IA39: The genetic basis of diffuse large B cell lymphoma.
Authors: Pasqualucci Laura 
Published: August 2015

Abstract
Diffuse large B cell lymphoma (DLBCL), the most common form of human lymphoma, is a heterogeneous neoplasm comprising multiple genetic, phenotypic and clinical subtypes, approximately 50% of which are incurable. These tumors may arise de novo or from the transformation of more indolent lymphomas, as observed in 30-40% of follicular lymphoma (FL) cases. Over the past decade, the introduction of next-generation sequencing technologies combined with genome-wide copy number analysis has allowed to comprehensively define the genomic landscape of this disease, leading to the identification of multiple genes and signaling pathways that are dysregulated by genetic lesions and represent potential targets for diagnosis and therapy. In addition to perturbations in the transcriptional control of apoptosis, differentiation and DNA damage responses or NF-κB activation, these efforts revealed the frequent targeting of genes implicated in chromatin remodeling and immune recognition/surveillance.
In particular, one of the most commonly disrupted programs in both de novo DLBCL, FL and transformed FL (tFL) comprises genes encoding histone/chromatin modifying enzymes, including methyltransferases (MLL2, EZH2) and acetyltransferases (CREBBP, EP300), which may play a central role during malignant transformation. Interestingly, sequential analysis of tumor samples during transformation of FL to tFL indicates that inactivating mutations of CREBBP and MLL2 are acquired early in the evolutionary history of a common mutated ancestral clone. The disruption of these genes by genetic alterations may thus contribute to malignant transformation by shaping the epigenetic landscape of the cancer cell as well as by perturbing specific biological programs, in part through the altered balance between acetylation-mediated activation of the p53 tumor suppressor and inactivation of the BCL6 proto-oncogene. This talk will cover recent advances in understanding the genetic basis of DLBCL, as revealed by in vitro and in vivo studies.
Citation Format: Laura Pasqualucci. The genetic basis of diffuse large B cell lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA39.
Abstract IA47: Epigenetic programming and therapy in germinal center derived B-cell lymphomas.
Authors: Melnick Ari M. 
Published: August 2015

Abstract
Diffuse Large B-cell Lymphomas (DLBCLs) are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability in order to generate a diverse set of clones of cells encoding high affinity antibodies. This accelerated micro-evolutionary process requires the concerted action of transcription and epigenetic factors that collectively reprogram B cells to overcome many of their normal checkpoint restraints and tolerate the various stresses associated with affinity maturation. The GC phenotype poses a significant risk of malignant transformation to B cells, which must accordingly balance suppression of checkpoints with suppression of pro-oncogenic genes. Epigenetic regulatory complexes play a critical role in lymphomagenesis. EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GCs, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCLs in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes. Epigenetic heterogeneity is associated with unfavorable outcome in B-cell lymphomas, suggesting that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that sensitizes lymphoma cells to more readily respond to chemotherapy. DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for the up-front treatment of patients with high-risk lymphomas.
Citation Format: Ari M. Melnick. Epigenetic programming and therapy in germinal center derived B-cell lymphomas. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA47.
Plasma Levels of Soluble Interleukin-2 Receptor α
Authors: Durda Peter , Sabourin Jeremy , Lange Ethan M. , Nalls Mike A. , Mychaleckyj Josyf C. , Jenny Nancy Swords , Li Jin , Walston Jeremy , Harris Tamara B. , Psaty Bruce M. , Valdar William , Liu Yongmei , Cushman Mary , Reiner Alex P. , Tracy Russell P. , Lange Leslie A. 
Published: August 2015

Objective—
Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

Approach and Results—

We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains
IL2RA
,
IL15RA
, and
RMB17
, that reached genome-wide significance (
P
<5×10
−8
). The most significant single-nucleotide polymorphism was rs7911500 (
P
=1.31×10
−75
). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

Conclusions—
These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.