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Transcriptional programming drives Ibrutinib-resistance evolution in mantlecell lymphoma.
Zhao, Xiaohong et al.
Ibrutinib, a bruton's tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated t...
Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes.
Musa J, Cidre-Aranaz F, Aynaud MM, Orth MF, Knott MML, Mirabeau O, Mazor G, Varon M, Hölting TLB, Grossetête S, Gartlgruber M, Surdez D, Gerke JS, Ohmura S, Marchetto A, Dallmayer M, Baldauf MC, Stein S, Sannino G, Li J, Romero-Pérez L, Westermann F, Hart
Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, ...
BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.
Zhao X, Ren Y, Lawlor M, Shah BD, Park PMC, Lwin T, Wang X, Liu K, Wang M, Gao J, Li T, Xu M, Silva AS, Lee K, Zhang T, Koomen JM, Jiang H, Sudalagunta PR, Meads MB, Cheng F, Bi C, Fu K, Fan H, Dalton WS, Moscinski LC, Shain KH, Sotomayor EM, Wang GG, Gra
Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss ...
P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress.
Bugai A, Quaresma AJC, Friedel CC, Lenasi T, Düster R, Sibley CR, Fujinaga K, Kukanja P, Hennig T, Blasius M, Geyer M, Ule J, Dölken L, Barborič M
DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcr...
A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation.
Roy K, Mitchell S, Liu Y, Ohta S, Lin YS, Metzig MO, Nutt SL, Hoffmann A
Humoral immunity depends on efficient activation of B cells and their subsequent differentiation into antibody-secreting cells (ASCs). The transcription factor NFκB cRel is critical for B cell proliferation, but incorporating its known regulatory interactions into a mathematical model of the ASC differentiatio...
TF-ChIP Method for Tissue-Specific Gene Targets.
Perna A, Alberi LA
Chromatin immunoprecipitation (ChIP) is an assay developed in order to define the dynamic nature of transcription processes. This method has been widely employed to identify methylated and acetylated DNA sequences in a variety of organs both in animals and humans. Nevertheless, this technique is significantly less e...
A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus.
Chen S, Luperchio TR, Wong X, Doan EB, Byrd AT, Roy Choudhury K, Reddy KL, Krangel MS
Tcrb locus V(D)J recombination is regulated by positioning at the nuclear periphery. Here, we used DamID to profile Tcrb locus interactions with the nuclear lamina at high resolution. We identified a lamina-associated domain (LAD) border composed of several CTCF-binding elements that segregates active non-LAD from i...
spe-43 is required for sperm activation in C. elegans.
Krauchunas AR, Mendez E, Ni JZ, Druzhinina M, Mulia A, Parry J, Gu SG, Stanfield GM, Singson A
Successful fertilization requires that sperm are activated prior to contacting an oocyte. In C. elegans, this activation process, called spermiogenesis, transforms round immobile spermatids into motile, fertilization-competent spermatozoa. We describe the phenotypic and genetic characterization of spe-43, a new comp...
Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis.
Khalkar P, Ali HA, Codó P, Argelich ND, Martikainen A, Arzenani MK, Lehmann S, Walfridsson J, Ungerstedt J, Fernandes AP
Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line ...