DF/HCC Program Affiliation

Lymphoma and Myeloma
Cancer Immunology

Research Abstract

The broad focus of the Alt laboratory is the elucidation of mechanisms involved in maintenance of genomic stability in mammalian cells. More specifically, the laboratory studies the mechanism and control of antigen receptor variable region gene assembly (VDJ recombination) in developing B and T lymphocytes and the mechanism of immunoglobulin heavy chain class switch recombination (CSR) and somatic hypermutation in activated mature B lymphocytes. Studies of the regulation of these processes involve elucidation of signaling events that lead to their activation, as well as elucidation of cis-acting chromosomal processes that effect accessibility of antigen receptor genes to lymphocyte specific DNA modification enzymes (i.e. RAG endonuclease and Activation Induced Deaminase). Mechanistic studies focus on the role of various, general DNA repair pathways in completing these lymphocyte-specific genetic alterations and in biochemical studies aimed at elucidating the molecular mechanisms by which Activation Induced Deaminase functions in somatic hypermutation and CSR and how the DNA damage response is involved in the completing the CSR reaction. The laboratory also studies how defects in VDJ recombination and CSR can lead to translocations associated with lymphoid malignancies. In this regard, a major current focus of the laboratory is the elucidation mechanisms by which the interplay of DNA repair and cell cycle checkpoint mechanisms acts to suppress genomic instability, lymphomas, and solid tumors. Laboratory approaches range from basic molecular genetics, biochemistry, proteomics, and genomics to gene-targeted mutation and the generation of novel animal-based approaches and models.

Publications

• Wu C, Ranganath S, Gleason M, Woodman BB, Borjeson TM, Alt FW, Bassing CH.Restriction of endogenous T cell antigen receptor beta rearrangements to Vbeta14 through selective recombination signal sequence modifications.Proc Natl Acad Sci U S A 2007 Mar 6;10
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• Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P.Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.EMBO J 2007 Apr 4;26(7):1913-23.
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• Zarrin AA, Del Vecchio C, Tseng E, Gleason M, Zarin P, Tian M, Alt FW.Antibody class switching mediated by yeast endonuclease-generated DNA breaks.Science 2007 Jan 19;315(5810):377-81.
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• Mostoslavsky G, Fabian AJ, Rooney S, Alt FW, Mulligan RC.Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer.Proc Natl Acad Sci U S A 2006 Oct 31;103(44):16406-11.
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• Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L.SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calori
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• Franco S, Alt FW, Manis JP.Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations.DNA Repair (Amst) 2006 Sep 8;5(9-10):1030-41.
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• Chaudhuri J, Khuong C, Alt FW.Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.Nature 2004 Jul 25.
  15273694
• Mills KD, Ferguson DO, Essers J, Eckersdorff M, Kanaar R, Alt FW.Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability.Genes Dev 2004 Jun 1;18(11):1283-92.
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• Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW.Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.Cell 2003 Aug 8;114(3):359-70.
  12914700
• Shinkura R, Tian M, Smith M, Chua K, Fujiwara Y, Alt FW.The influence of transcriptional orientation on endogenous switch region function.Nat Immunol 2003 May;4(5):435-41.
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• Rooney S, Sekiguchi J, Zhu C, Cheng HL, Manis J, Whitlow S, DeVido J, Foy D, Chaudhuri J, Lombard D, Alt FW.Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice.Mol Cell 2002 Dec;10(6):1379-90.
  12504013
• Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW.Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.Cell 2002;109:811-821.
• Bassing CH, Alt FW, Hughes MM, D'Auteuil M, Wehrly TD, Woodman BB, Gärtner F, White JM, Davidson L, Sleckman BP.Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule.Nature 2000 Jun 1;405(6786):583-6.
  10850719
• Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW.Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development.Nature 2000 Apr 20;404(6780):897-900.
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