Research

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John Manis, MD

John Manis, MD
Department:
Laboratory Medicine Research
Hospital Title:
Associate Director Transfusion Medicine
Academic Title:
Assistant Professor of Pathology, Harvard Medical School
Contact:
617-919-2618
Contact Via Email
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Research Overview

The Manis lab focuses on the development of the immune system. One area of work focuses on the basic mechanisms that control programmed DNA breaks in B cells of the immune system.  Errors in the repair of programmed immune system breaks lead to immunodeficiency and can lead to cancers including lymphoma.  The laboratory has expertise in generating gene-targeted mouse embryonic stem cells and mice to study immune system defects.  Another area of focus is in developing mouse models for human primary immunodeficiency syndromes.  Presently, a mouse model of Job's Syndrome, replicating autosomal-dominant Hyper IgE syndrome due to defective Stat 3 is being examined to understand lineage specific contributions to the disease.

Publications

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  1. Jabara HH, Lee JJ, Janssen E, Ullas S, Liadaki K, Garibyan L, Benson H, Sannikova T, Bram R, Hammarstrom L, Cruz AC, Siegel R, Manis J, Malley R, Geha RS. Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice. J Allergy Clin Immunol. 2016 Sep 5.
  2. Manis JP, Silberstein LE. Platelet refractoriness: it's not the B-all and end-all. Blood. 2016 Apr 7; 127(14):1740-1.
  3. Ott de Bruin L, Yang W, Capuder K, Lee YN, Antolini M, Meyers R, Gellert M, Musunuru K, Manis J, Notarangelo L. Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes. Oncotarget. 2016 Mar 15; 7(11):12962-74.
  4. Frugoni F, Dobbs K, Felgentreff K, Aldhekri H, Al Saud BK, Arnaout R, Ali AA, Abhyankar A, Alroqi F, Giliani S, Ojeda MM, Tsitsikov E, Pai SY, Casanova JL, Notarangelo LD, Manis JP. A novel mutation in the POLE2 gene causing combined immunodeficiency. J Allergy Clin Immunol. 2016 Feb; 137(2):635-638.e1.
  5. Kumar L, Chou J, Yee CS, Borzutzky A, Vollmann EH, von Andrian UH, Park SY, Hollander G, Manis JP, Poliani PL, Geha RS. Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med. 2014 May 5; 211(5):929-42.
  6. Janssen E, Ozcan E, Liadaki K, Jabara HH, Manis J, Ullas S, Akira S, Fitzgerald KA, Golenbock DT, Geha RS. TRIF signaling is essential for TLR4-driven IgE class switching. J Immunol. 2014 Mar 15; 192(6):2651-8.
  7. Park SY, Wolfram P, Canty K, Harley B, Nombela-Arrieta C, Pivarnik G, Manis J, Beggs HE, Silberstein LE. Focal adhesion kinase regulates the localization and retention of pro-B cells in bone marrow microenvironments. J Immunol. 2013 Feb 1; 190(3):1094-102.
  8. Wesemann DR, Magee JM, Boboila C, Calado DP, Gallagher MP, Portuguese AJ, Manis JP, Zhou X, Recher M, Rajewsky K, Notarangelo LD, Alt FW. Immature B cells preferentially switch to IgE with increased direct Sµ to Se recombination. J Exp Med. 2011 Dec 19; 208(13):2733-46.
  9. Green MR, Monti S, Dalla-Favera R, Pasqualucci L, Walsh NC, Schmidt-Supprian M, Kutok JL, Rodig SJ, Neuberg DS, Rajewsky K, Golub TR, Alt FW, Shipp MA, Manis JP. Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. Proc Natl Acad Sci U S A. 2011 Feb 15; 108(7):2873-8.
  10. Perlot T, Pawlitzky I, Manis JP, Zarrin AA, Brodeur PH, Alt FW. Analysis of mice lacking DNaseI hypersensitive sites at the 5' end of the IgH locus. PLoS One. 2010 Nov 15; 5(11):e13992.
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  12. Cheng HL, Vuong BQ, Basu U, Franklin A, Schwer B, Astarita J, Phan RT, Datta A, Manis J, Alt FW, Chaudhuri J. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2717-22.
  13. Wang JH, Alt FW, Gostissa M, Datta A, Murphy M, Alimzhanov MB, Coakley KM, Rajewsky K, Manis JP, Yan CT. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med. 2008 Dec 22; 205(13):3079-90.
  14. Jolly CJ, Cook AJ, Manis JP. Fixing DNA breaks during class switch recombination. J Exp Med. 2008 Mar 17; 205(3):509-13.
  15. Manis JP. Knock out, knock in, knock down--genetically manipulated mice and the Nobel Prize. N Engl J Med. 2007 Dec 13; 357(24):2426-9.
  16. Jabara HH, Chaudhuri J, Dutt S, Dedeoglu F, Weng Y, Murphy MM, Franco S, Alt FW, Manis J, Geha RS. B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE. J Allergy Clin Immunol. 2008 Jan; 121(1):191-196.e2.
  17. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007 Sep 27; 449(7161):478-82.
  18. Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S, Perlot T, Vuong B, Wang J, Phan RT, Datta A, Manis J, Alt FW. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol. 2007; 94:157-214.
  19. 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.
  20. Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, Celeste A, Manis JP, van Deursen J, Nussenzweig A, Paull TT, Alt FW, Chen J. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell. 2006 Jan 20; 21(2):187-200.
  21. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell. 2006 Jan 20; 21(2):201-14.
  22. Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, Li G, Schrum JP, Manis JP, Alt FW. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature. 2005 Nov 24; 438(7067):508-11.
  23. Rooney S, Alt FW, Sekiguchi J, Manis JP. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc Natl Acad Sci U S A. 2005 Feb 15; 102(7):2471-5.
  24. Manis JP, Morales JC, Xia Z, Kutok JL, Alt FW, Carpenter PB. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol. 2004 May; 5(5):481-7.
  25. Rooney S, Sekiguchi J, Whitlow S, Eckersdorff M, Manis JP, Lee C, Ferguson DO, Alt FW. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc Natl Acad Sci U S A. 2004 Feb 24; 101(8):2410-5.
  26. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, Chua KF. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A. 2003 Sep 16; 100(19):10794-9.
  27. 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.
  28. Manis JP, Alt FW. Novel antibody switching defects in human patients. J Clin Invest. 2003 Jul; 112(1):19-22.
  29. Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med. 2003 May 5; 197(9):1213-9.
  30. Manis JP, Michaelson JS, Birshtein BK, Alt FW. Elucidation of a downstream boundary of the 3' IgH regulatory region. Mol Immunol. 2003 Jan; 39(12):753-60.
  31. 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.
  32. Dudley DD, Manis JP, Zarrin AA, Kaylor L, Tian M, Alt FW. Internal IgH class switch region deletions are position-independent and enhanced by AID expression. Proc Natl Acad Sci U S A. 2002 Jul 23; 99(15):9984-9.
  33. 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 Jun 28; 109(7):811-21.
  34. Chua KF, Alt FW, Manis JP. The function of AID in somatic mutation and class switch recombination: upstream or downstream of DNA breaks. J Exp Med. 2002 May 6; 195(9):F37-41.
  35. Manis JP, Dudley D, Kaylor L, Alt FW. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity. 2002 Apr; 16(4):607-17.
  36. Manis JP, Tian M, Alt FW. Mechanism and control of class-switch recombination. Trends Immunol. 2002 Jan; 23(1):31-9.
  37. Ferguson DO, Sekiguchi JM, Frank KM, Gao Y, Sharpless NE, Gu Y, Manis J, DePinho RA, Alt FW. The interplay between nonhomologous end-joining and cell cycle checkpoint factors in development, genomic stability, and tumorigenesis. Cold Spring Harb Symp Quant Biol. 2000; 65:395-403.
  38. Manis JP. Precursors of Hodgkin's disease and B-cell lymphomas. N Engl J Med. 1999 Apr 22; 340(16):1280-2.
  39. Seidl KJ, Manis JP, Bottaro A, Zhang J, Davidson L, Kisselgof A, Oettgen H, Alt FW. Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. Proc Natl Acad Sci U S A. 1999 Mar 16; 96(6):3000-5.
  40. Manis JP, van der Stoep N, Tian M, Ferrini R, Davidson L, Bottaro A, Alt FW. Class switching in B cells lacking 3' immunoglobulin heavy chain enhancers. J Exp Med. 1998 Oct 19; 188(8):1421-31.
  41. Lansford R, Manis JP, Sonoda E, Rajewsky K, Alt FW. Ig heavy chain class switching in Rag-deficient mice. Int Immunol. 1998 Mar; 10(3):325-32.
  42. Manis J, Schwartz RS. Agammaglobulinemia and insights into B-cell differentiation. N Engl J Med. 1996 Nov 14; 335(20):1523-5.
  43. 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.
  44. Manis JP, Gu Y, Lansford R, Sonoda E, Ferrini R, Davidson L, Rajewsky K, Alt FW. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med. 1998 Jun 15; 187(12):2081-9.
  45. Boboila C, Yan C, Wesemann DR, Jankovic M, Wang JH, Manis J, Nussenzweig A, Nussenzweig M, Alt FW. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med. 2010 Feb 15; 207(2):417-27.
  46. Wuerffel R, Wang L, Grigera F, Manis J, Selsing E, Perlot T, Alt FW, Cogne M, Pinaud E, Kenter AL. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity. 2007 Nov; 27(5):711-22.
  47. Zhang T, Franklin A, Boboila C, McQuay A, Gallagher MP, Manis JP, Khamlichi AA, Alt FW. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci U S A. 2010 Feb 16; 107(7):3040-5.
  48. Takeyama K, Monti S, Manis JP, Dal Cin P, Getz G, Beroukhim R, Dutt S, Aster JC, Alt FW, Golub TR, Shipp MA. Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. Oncogene. 2008 Jan 10; 27(3):318-22.
  49. Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell. 2000 Jun; 5(6):993-1002.
  50. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001 Jul 19; 412(6844):300-7.
  51. Sekiguchi JM, Gao Y, Gu Y, Frank K, Sun Y, Chaudhuri J, Zhu C, Cheng HL, Manis J, Ferguson D, Davidson L, Greenberg ME, Alt FW. Nonhomologous end-joining proteins are required for V(D)J recombination, normal growth, and neurogenesis. Cold Spring Harb Symp Quant Biol. 1999; 64:169-81.
  52. Gu Y, Seidl KJ, Rathbun GA, Zhu C, Manis JP, van der Stoep N, Davidson L, Cheng HL, Sekiguchi JM, Frank K, Stanhope-Baker P, Schlissel MS, Roth DB, Alt FW. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity. 1997 Nov; 7(5):653-65.
  53. Senoo M, Manis JP, Alt FW, McKeon F. p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. Cancer Cell. 2004 Jul; 6(1):85-9.
  54. Morales JC, Franco S, Murphy MM, Bassing CH, Mills KD, Adams MM, Walsh NC, Manis JP, Rassidakis GZ, Alt FW, Carpenter PB. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc Natl Acad Sci U S A. 2006 Feb 28; 103(9):3310-5.
  55. Sherman MH, Kuraishy AI, Deshpande C, Hong JS, Cacalano NA, Gatti RA, Manis JP, Damore MA, Pellegrini M, Teitell MA. AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol Cell. 2010 Sep 24; 39(6):873-85.
  56. Yan Q, Xu R, Zhu L, Cheng X, Wang Z, Manis J, Shipp MA. BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol Cell Biol. 2013 Feb; 33(4):845-57.
  57. Yan Q, Dutt S, Xu R, Graves K, Juszczynski P, Manis JP, Shipp MA. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol Cell. 2009 Oct 9; 36(1):110-20.
  58. Recher M, Burns SO, de la Fuente MA, Volpi S, Dahlberg C, Walter JE, Moffitt K, Mathew D, Honke N, Lang PA, Patrizi L, Falet H, Keszei M, Mizui M, Csizmadia E, Candotti F, Nadeau K, Bouma G, Delmonte OM, Frugoni F, Fomin AB, Buchbinder D, Lundequist EM, Massaad MJ, Tsokos GC, Hartwig J, Manis J, Terhorst C, Geha RS, Snapper S, Lang KS, Malley R, Westerberg L, Thrasher AJ, Notarangelo LD. B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood. 2012 Mar 22; 119(12):2819-28.
  59. Le Y, Zhu BM, Harley B, Park SY, Kobayashi T, Manis JP, Luo HR, Yoshimura A, Hennighausen L, Silberstein LE. SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis. Immunity. 2007 Nov; 27(5):811-23.
  60. Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012 May 13; 13(6):612-20.
  61. Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, Manis J, Im H, Gallagher JE, Phanstiel DH, Euskirchen G, Lacroute P, Bettinger K, Moratto D, Weinacht K, Montin D, Gallo E, Mangili G, Porta F, Notarangelo LD, Pedretti S, Al-Herz W, Alfahdli W, Comeau AM, Traister RS, Pai SY, Carella G, Facchetti F, Nadeau KC, Snyder M, Notarangelo LD. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013 Sep; 132(3):656-664.e17.
  62. Felgentreff K, Du L, Weinacht KG, Dobbs K, Bartish M, Giliani S, Schlaeger T, DeVine A, Schambach A, Woodbine LJ, Davies G, Baxi SN, van der Burg M, Bleesing J, Gennery A, Manis J, Pan-Hammarström Q, Notarangelo LD. Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2014 Jun 17; 111(24):8889-94.
  63. Mooster JL, Le Bras S, Massaad MJ, Jabara H, Yoon J, Galand C, Heesters BA, Burton OT, Mattoo H, Manis J, Geha RS. Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in I?Ba. J Exp Med. 2015 Feb 9; 212(2):185-202.
  64. Felgentreff K, Lee YN, Frugoni F, Du L, van der Burg M, Giliani S, Tezcan I, Reisli I, Mejstrikova E, de Villartay JP, Sleckman BP, Manis J, Notarangelo LD. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J Allergy Clin Immunol. 2015 Jul; 136(1):140-150.e7.
  65. Dong J, Panchakshari RA, Zhang T, Zhang Y, Hu J, Volpi SA, Meyers RM, Ho YJ, Du Z, Robbiani DF, Meng F, Gostissa M, Nussenzweig MC, Manis JP, Alt FW. Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature. 2015 Sep 3; 525(7567):134-9.
  66. Massaad MJ, Zhou J, Tsuchimoto D, Chou J, Jabara H, Janssen E, Glauzy S, Olson BG, Morbach H, Ohsumi TK, Schmitz K, Kyriacos M, Kane J, Torisu K, Nakabeppu Y, Notarangelo LD, Chouery E, Megarbane A, Kang PB, Al-Idrissi E, Aldhekri H, Meffre E, Mizui M, Tsokos GC, Manis JP, Al-Herz W, Wallace SS, Geha RS. Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. J Clin Invest. 2016 Nov 01; 126(11):4219-4236.
  67. Hartlerode AJ, Willis NA, Rajendran A, Manis JP, Scully R. Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet. 2016 Nov; 12(11):e1006410.
  68. Manis J, Schachter D. Active transport of iron by intestine: effect of erythropoiesis stimulated by phenylhydrazine. Nature. 1966 Mar 26; 209(5030):1356.
  69. Yoshino Y, Manis J, Schachter D. Actinomycin D and the regulation of apoferritin synthesis in rat liver. Nature. 1966 Apr 30; 210(5035):538-9.
  70. Manis J. Active transport of iron by intestine: selective genetic defect in the mouse. Nature. 1970 Jul 25; 227(5256):385-6.
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