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237


AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis

Teater, Matt; Dominguez, Pilar M; Redmond, David; Chen, Zhengming; Ennishi, Daisuke; Scott, David W; Cimmino, Luisa; Ghione, Paola; Chaudhuri, Jayanta; Gascoyne, Randy D; Aifantis, Iannis; Inghirami, Giorgio; Elemento, Olivier; Melnick, Ari; Shaknovich, Rita
Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.
PMCID:5768781
PMID: 29335468
ISSN: 2041-1723
CID: 2915552

Dynamic 3d chromosomal landscapes in acute leukemia [Meeting Abstract]

Thandapani, Palaniraja; Kloetgen, Andreas; Lazaris, Charalampos; Chen, Xufeng; Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Aifantis, Iannis
ISI:000468819500362
ISSN: 0008-5472
CID: 5185512

Apoptosis, Up the Ante

Thandapani, Palaniraja; Aifantis, Iannis
The clinical success of the BH3-mimetic venetoclax has generated increasing interest to target BCL2 family proteins in oncology. In this issue of Cancer Cell, Reyna and colleagues demonstrate the potential of a pharmacological activator of the pro-apoptotic protein BAX to suppress acute myeloid leukemia both alone and together with venetoclax.
PMID: 29017053
ISSN: 1878-3686
CID: 2731692

Characterization of Treatment Effects on the Tumor Microenvironment Using Single Cell RNA Sequencing [Meeting Abstract]

Oh, P; Hockemeyer, K; Satija, R; Aifantis, I
ISI:000411559107252
ISSN: 1879-355x
CID: 2767812

Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite

Wang, Eric; Aifantis, Ioannis
In this study, McKeown and colleagues carried out a genome-wide characterization and stratification of the enhancer landscape in acute myeloid leukemia (AML). The authors' analysis led to the discovery of a novel RARA superenhancer found in a subset of patients with AML, rendering these leukemia cells highly sensitive to SY-1425, a highly potent RARA agonist able to induce myeloid differentiation in these high-expressing RARA AML subtypes. Cancer Discov; 7(10); 1065-6. (c)2017 AACR.See related article by McKeown et al., p. 1136.
PMCID:5744667
PMID: 28974530
ISSN: 2159-8290
CID: 2719652

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao; Yoshimi, Akihide; Martin, Gaelle H; Wang, Jingjing; Ng, Victor; Xia, Bo; Witkowski, Matthew T; Mitchell-Flack, Marisa; Grillo, Isabella; Bakogianni, Sofia; Ndiaye-Lobry, Delphine; Martin, Miguel Torres; Guillamot, Maria; Banh, Robert S; Xu, Mingjiang; Figueroa, Maria E; Dickins, Ross A; Abdel-Wahab, Omar; Park, Christopher Y; Tsirigos, Aristotelis; Neel, Benjamin G; Aifantis, Iannis
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and alpha-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.
PMCID:5755977
PMID: 28823558
ISSN: 1097-4172
CID: 2676732

PRC2-mediated silencing of circRNA CDR1as drives miR-7- independent melanoma metastasis [Meeting Abstract]

Hanniford, D; Moubarak, R; Imig, J; Ulloa, A; Sendra, B S; Karz, A; Osman, I; Aifantis, I; Hernando, E
Circular RNAs are a novel class of non-coding RNAs with functions that remain poorly characterized in normal and pathological conditions. CDR1as is a non-canonical circRNA observed to act as a sponge for miR-7 in brain tissues. Analysis of RNA-seq data of melanocytes and melanoma cell lines and short-term cultures revealed loss of CDR1as expression as a hallmark of melanoma cells. We confirmed silencing of CDR1as in melanoma cells and tissues by RT-qPCR using divergent primers. Clinically, we observed CDR1as loss associated with metastatic progression and poor patient outcomes in a cohort of fresh-frozen melanoma tissue samples. Depletion of CDR1as in melanoma cell lines enhanced invasion in vitro and lung metastasis in vivo, demonstrating functional significance of CDR1as silencing. Surprisingly, CDR1as depletion had no clear effect on miR-7 activity in melanoma cells, and miR-7 inhibition was insufficient to rescue CDR1as silencing-induced invasion. Moreover, GSEA analyses of proteomic profiling of melanoma cells depleted of CDR1as revealed reductions of proteins involved in oxidative phosphorylation (OXPHOS) and mitochondrial function, suggesting CDR1as loss may alter metabolism of melanoma cells. Mining of CLIP-Seq data sets and subsequent RIP-PCR revealed direct interactions of CDR1as with the IGF2BP family of proteins and TAR
EMBASE:618565797
ISSN: 1538-7445
CID: 2752502

AICDA DRIVES EPIGENETIC HETEROGENEITY IN GERMINAL CENTER-DERIVED LYMPHOMAS AND ACCELERATES LYMPHOMAGENESIS [Meeting Abstract]

Dominguez, PM; Teater, M; Redmond, D; Chen, Z; Ennishi, D; Scott, DW; Cimmino, L; Ghione, P; Chaudhuri, J; Gascoyne, RD; Aifantis, I; Inghirami, G; Elemento, O; Melnick, A; Shaknovich, R
ISI:000404127001192
ISSN: 0390-6078
CID: 2624712

lncRNA-screen: an interactive platform for computationally screening long non-coding RNAs in large genomics datasets

Gong, Yixiao; Huang, Hsuan-Ting; Liang, Yu; Trimarchi, Thomas; Aifantis, Iannis; Tsirigos, Aristotelis
BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a class of factors that are important for regulating development and cancer. Computational prediction of lncRNAs from ultra-deep RNA sequencing has been successful in identifying candidate lncRNAs. However, the complexity of handling and integrating different types of genomics data poses significant challenges to experimental laboratories that lack extensive genomics expertise. RESULT: To address this issue, we have developed lncRNA-screen, a comprehensive pipeline for computationally screening putative lncRNA transcripts over large multimodal datasets. The main objective of this work is to facilitate the computational discovery of lncRNA candidates to be further examined by functional experiments. lncRNA-screen provides a fully automated easy-to-run pipeline which performs data download, RNA-seq alignment, assembly, quality assessment, transcript filtration, novel lncRNA identification, coding potential estimation, expression level quantification, histone mark enrichment profile integration, differential expression analysis, annotation with other type of segmented data (CNVs, SNPs, Hi-C, etc.) and visualization. Importantly, lncRNA-screen generates an interactive report summarizing all interesting lncRNA features including genome browser snapshots and lncRNA-mRNA interactions based on Hi-C data. CONCLUSION: lncRNA-screen provides a comprehensive solution for lncRNA discovery and an intuitive interactive report for identifying promising lncRNA candidates. lncRNA-screen is available as open-source software on GitHub.
PMCID:5458484
PMID: 28583068
ISSN: 1471-2164
CID: 2590412

RNA-binding proteins, the guardians of the marginal zone

Thandapani, Palaniraja; Aranda-Orgilles, Beatriz; Aifantis, Iannis
PMID: 28518167
ISSN: 1529-2916
CID: 2562292