John P. Manis, MD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2618
Fax: (617) 730-0217


manis@enders.tch.harvard.edu

John P. Manis, MD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Pathology, Harvard Medical School
  • Investigator, Joint Program in Transfusion Medicine, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our lab focuses on the response to and repair of programmed DNA breaks that occur during B cell development. B cells undergo programmed DNA breaks during a normal immune response in order to generate higher affinity antibodies with specialized functions. Immunoglobulin class switch recombination (CSR) alters the effector function of antibodies without a change in antigen specificity, emlpoying a process that requires DNA double strand breaks. Errors in the repair of these programmed double strand breaks required for CSR are thought to result in oncogenic translocations commonly seen in human B cell lymphoma. We seek to elucidate the role of the DNA damage response (DDR) pathway in the development of germinal center B cell lymphoma, focusing on members of the DDR pathway including ATM, 53BP1, and H2AX. The DDR pathway is triggered early after DNA damage and is found to be activated during the intial phases of carcinogenesis. By examining the DDR both in normal human B cell populations within a germinal center reaction, and in lymphoma samples, we can gain valuable insights into the alterations which predispose to lymphomagenesis and additionally allow for the development of clinically useful diagnostic and prognostic tools.

Publications

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  • 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虜B留. J Exp Med 2015; 212:185-202. PubMed
  • 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. PubMed
  • 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; 190:1094-102. PubMed
  • 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; 33:845-57. PubMed
  • 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; 108:2873-8. PubMed
  • 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; 39:873-85. PubMed
  • 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; 107:3040-5. PubMed
  • 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; 207:417-27. PubMed
  • 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; 5:e13992. PubMed
  • 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; 36:110-20. PubMed
  • 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; 106:2717-22. PubMed
  • 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; 205:3079-90. PubMed
  • Jolly CJ, Cook AJ, Manis JP. Fixing DNA breaks during class switch recombination. J Exp Med 2008; 205:509-13. PubMed
  • Takeyama K, Monti S, Manis JP, Cin PD, 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; 27:318-22. PubMed
  • Manis JP. Knock out, knock in, knock down--genetically manipulated mice and the Nobel Prize. N Engl J Med 2007; 357:2426-9. PubMed
  • 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; 27:711-22. PubMed
  • 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; 27:811-23. PubMed
  • 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; 449:478-82. PubMed
  • Franco S, Alt FW, Manis JP. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 2006; 5:1030-41. PubMed
  • 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; 103:3310-5. PubMed
  • 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; 21:201-14. PubMed
  • 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.
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