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Frederick W Alt

Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 23, 2017: Nature
Laurent Verkoczy, Frederick W Alt, Ming Tian
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb development. Since 2010, immunoglobulin knockin (KI) technology, involving inserting functional rearranged human variable exons into the mouse IgH and IgL loci has been used to express bnAbs in mice...
January 2017: Immunological Reviews
Liang Chen, Lijuan Zhao, Frederick W Alt, Michael S Krangel
Chromatin looping mediated by the CCCTC binding factor (CTCF) regulates V(D)J recombination at Ag receptor loci. CTCF-mediated looping can influence recombination signal sequence (RSS) accessibility by regulating enhancer activation of germline promoters. CTCF-mediated looping has also been shown to limit directional tracking of the RAG recombinase along chromatin, and to regulate long-distance interactions between RSSs, independent of the RAG recombinase. However, in all prior instances in which CTCF-mediated looping was shown to influence V(D)J recombination, it was not possible to fully resolve the relative contributions to the V(D)J recombination phenotype of changes in accessibility, RAG tracking, and RAG-independent long-distance interactions...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ming Tian, Cheng Cheng, Xuejun Chen, Hongying Duan, Hwei-Ling Cheng, Mai Dao, Zizhang Sheng, Michael Kimble, Lingshu Wang, Sherry Lin, Stephen D Schmidt, Zhou Du, M Gordon Joyce, Yiwei Chen, Brandon J DeKosky, Yimin Chen, Erica Normandin, Elizabeth Cantor, Rita E Chen, Nicole A Doria-Rose, Yi Zhang, Wei Shi, Wing-Pui Kong, Misook Choe, Amy R Henry, Farida Laboune, Ivelin S Georgiev, Pei-Yi Huang, Suvi Jain, Andrew T McGuire, Eric Georgeson, Sergey Menis, Daniel C Douek, William R Schief, Leonidas Stamatatos, Peter D Kwong, Lawrence Shapiro, Barton F Haynes, John R Mascola, Frederick W Alt
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors...
September 8, 2016: Cell
Vipul Kumar, Frederick W Alt, Richard L Frock
Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Lijuan Zhao, Richard L Frock, Zhou Du, Jiazhi Hu, Liang Chen, Michael S Krangel, Frederick W Alt
T cell antigen receptor δ (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination events in developing γδ thymocytes. Here, we use linear amplification-mediated high-throughput genome-wide translocation sequencing (LAM-HTGTS) to map hundreds of thousands of RAG-initiated Tcrd D segment (Trdd1 and Trdd2) rearrangements in CD4(-)CD8(-) double-negative thymocyte progenitors differentiated in vitro from bone marrow-derived hematopoietic stem cells. We find that Trdd2 joins directly to Trdv, Trdd1, and Trdj segments, whereas Trdd1 joining is ordered with joining to Trdd2, a prerequisite for further rearrangement...
August 22, 2016: Journal of Experimental Medicine
Sherry G Lin, Zhaoqing Ba, Zhou Du, Yu Zhang, Jiazhi Hu, Frederick W Alt
Developing B lymphocytes undergo V(D)J recombination to assemble germ-line V, D, and J gene segments into exons that encode the antigen-binding variable region of Ig heavy (H) and light (L) chains. IgH and IgL chains associate to form the B-cell receptor (BCR), which, upon antigen binding, activates B cells to secrete BCR as an antibody. Each of the huge number of clonally independent B cells expresses a unique set of IgH and IgL variable regions. The ability of V(D)J recombination to generate vast primary B-cell repertoires results from a combinatorial assortment of large numbers of different V, D, and J segments, coupled with diversification of the junctions between them to generate the complementary determining region 3 (CDR3) for antigen contact...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ilan Bank, Ronald A DePinho, Michael B Brenner, Judy Cassimeris, Frederick W Alt, Leonard Chess
No abstract text is available yet for this article.
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jiazhi Hu, Robin M Meyers, Junchao Dong, Rohit A Panchakshari, Frederick W Alt, Richard L Frock
Unbiased, high-throughput assays for detecting and quantifying DNA double-stranded breaks (DSBs) across the genome in mammalian cells will facilitate basic studies of the mechanisms that generate and repair endogenous DSBs. They will also enable more applied studies, such as those to evaluate the on- and off-target activities of engineered nucleases. Here we describe a linear amplification-mediated high-throughput genome-wide sequencing (LAM-HTGTS) method for the detection of genome-wide 'prey' DSBs via their translocation in cultured mammalian cells to a fixed 'bait' DSB...
May 2016: Nature Protocols
Bjoern Schwer, Pei-Chi Wei, Amelia N Chang, Jennifer Kao, Zhou Du, Robin M Meyers, Frederick W Alt
High-throughput, genome-wide translocation sequencing (HTGTS) studies of activated B cells have revealed that DNA double-strand breaks (DSBs) capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes. We used the HTGTS approach to investigate whether a similar phenomenon occurs in primary neural stem/progenitor cells (NSPCs). We report that breakpoint junctions indeed are enriched around TSSs that were determined to be active by global run-on sequencing analyses of NSPCs...
February 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
Pei-Chi Wei, Amelia N Chang, Jennifer Kao, Zhou Du, Robin M Meyers, Frederick W Alt, Bjoern Schwer
Repair of DNA double-strand breaks (DSBs) by non-homologous end joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs), and remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites...
February 11, 2016: Cell
Peter Scully, Jie Zhao, Sujuan Ba
The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)--a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients...
February 3, 2016: Chinese Journal of Cancer
Armand Garot, Marie Marquet, Alexis Saintamand, Sébastien Bender, Sandrine Le Noir, Pauline Rouaud, Claire Carrion, Zéliha Oruc, Anne-Gaëlle Bébin, Jeanne Moreau, Kevin Lebrigand, Yves Denizot, Frederick W Alt, Michel Cogné, Eric Pinaud
As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3' regulatory region (3'RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3'RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasi-palindromic structure...
February 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jiazhi Hu, Yu Zhang, Lijuan Zhao, Richard L Frock, Zhou Du, Robin M Meyers, Fei-long Meng, David G Schatz, Frederick W Alt
RAG initiates antibody V(D)J recombination in developing lymphocytes by generating "on-target" DNA breaks at matched pairs of bona fide recombination signal sequences (RSSs). We employ bait RAG-generated breaks in endogenous or ectopically inserted RSS pairs to identify huge numbers of RAG "off-target" breaks. Such breaks occur at the simple CAC motif that defines the RSS cleavage site and are largely confined within convergent CTCF-binding element (CBE)-flanked loop domains containing bait RSS pairs. Marked orientation dependence of RAG off-target activity within loops spanning up to 2 megabases implies involvement of linear tracking...
November 5, 2015: Cell
Leng-Siew Yeap, Joyce K Hwang, Zhou Du, Robin M Meyers, Fei-Long Meng, Agnė Jakubauskaitė, Mengyuan Liu, Vinidhra Mani, Donna Neuberg, Thomas B Kepler, Jing H Wang, Frederick W Alt
In activated B lymphocytes, AID initiates antibody variable (V) exon somatic hypermutation (SHM) for affinity maturation in germinal centers (GCs) and IgH switch (S) region DNA breaks (DSBs) for class-switch recombination (CSR). To resolve long-standing questions, we have developed an in vivo assay to study AID targeting of passenger sequences replacing a V exon. First, we find AID targets SHM hotspots within V exon and S region passengers at similar frequencies and that the normal SHM process frequently generates deletions, indicating that SHM and CSR employ the same mechanism...
November 19, 2015: Cell
Junchao Dong, Rohit A Panchakshari, Tingting Zhang, Yu Zhang, Jiazhi Hu, Sabrina A Volpi, Robin M Meyers, Yu-Jui Ho, Zhou Du, Davide F Robbiani, Feilong Meng, Monica Gostissa, Michel C Nussenzweig, John P Manis, Frederick W Alt
During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cμ constant region exons. In mice, six additional sets of constant region exons (CHs) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D)J and Cμ exons. Long repetitive switch (S) regions precede Cμ and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cμ with a downstream CH (ref...
September 3, 2015: Nature
Joyce K Hwang, Frederick W Alt, Leng-Siew Yeap
The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity...
February 2015: Microbiology Spectrum
Zhaoqing Ba, Fei-Long Meng, Monica Gostissa, Pei-Yi Huang, Qiang Ke, Zhe Wang, Mai N Dao, Yuko Fujiwara, Klaus Rajewsky, Baochun Zhang, Frederick W Alt
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of α/β and γ/δ T cells ("CLT" mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles...
June 2015: Cancer Immunology Research
Baochun Zhang, Dinis Pedro Calado, Zhe Wang, Sebastian Fröhler, Karl Köchert, Yu Qian, Sergei B Koralov, Marc Schmidt-Supprian, Yoshiteru Sasaki, Christine Unitt, Scott Rodig, Wei Chen, Riccardo Dalla-Favera, Frederick W Alt, Laura Pasqualucci, Klaus Rajewsky
Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation...
May 5, 2015: Cell Reports
Wenxia Jiang, Brian J Lee, Chen Li, Richard L Dubois, Monica Gostissa, Frederick W Alt, Shan Zha
Ataxia telangiectasia mutated (ATM) is a protein kinase and a master regulator of DNA-damage responses. Germline ATM inactivation causes ataxia-telangiectasia (A-T) syndrome with severe lymphocytopenia and greatly increased risk for T-cell lymphomas/leukemia. Both A-T and T-cell prolymphoblastic leukemia patients with somatic mutations of ATM frequently carry inv(14;14) between the T-cell receptor α/δ (TCRα/δ) and immunoglobulin H loci, but the molecular origin of this translocation remains elusive. ATM(-/-) mice recapitulate lymphocytopenia of A-T patients and routinely succumb to thymic lymphomas with t(12;14) translocation, syntenic to inv(14;14) in humans...
April 23, 2015: Blood
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