1932

Abstract

Genomic analyses of diffuse large B cell lymphoma (DLBCL) are revealing the genetic and phenotypic heterogeneity of these aggressive lymphomas. In part, this heterogeneity reflects the existence of distinct genetic subtypes that acquire characteristic constellations of somatic genetic alterations to converge on the DLBCL phenotype. In parallel, functional genomic screens and proteomic analyses have identified multiprotein assemblies that coordinate oncogenic survival signaling in DLBCL. In this review, we merge these recent insights into a unified conceptual framework with implications for the design of precision medicine trials in DLBCL.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030518-055734
2019-03-04
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/3/1/annurev-cancerbio-030518-055734.html?itemId=/content/journals/10.1146/annurev-cancerbio-030518-055734&mimeType=html&fmt=ahah

Literature Cited

  1. Alizadeh A, Eisen M, Botstein D, Brown PO, Staudt LM 1998. Probing lymphocyte biology by genomic-scale gene expression analysis. J. Clin. Immunol. 18:373–79
    [Google Scholar]
  2. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS et al. 2000. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–11
    [Google Scholar]
  3. Basso K, Dalla-Favera R 2012. Roles of BCL6 in normal and transformed germinal center B cells. Immunol. Rev. 247:172–83
    [Google Scholar]
  4. Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL et al. 2013. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23:677–92
    [Google Scholar]
  5. Beguelin W, Teater M, Gearhart MD, Calvo Fernandez MT, Goldstein RL et al. 2016. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell 30:197–213
    [Google Scholar]
  6. Boice M, Salloum D, Mourcin F, Sanghvi V, Amin R et al. 2016. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell 167:405–18.e13
    [Google Scholar]
  7. Braggio E, Van Wier S, Ojha J, McPhail ER, Assmann Y et al. 2015. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas. Clin. Cancer Res. 21:3986–94
    [Google Scholar]
  8. Bruno A, Boisselier B, Labreche K, Marie Y, Polivka M et al. 2014. Mutational analysis of primary central nervous system lymphoma. Oncotarget 5:5065–75
    [Google Scholar]
  9. Bruscaggin A, Monti S, Arcaini L, Ramponi A, Rattotti S et al. 2014. Molecular lesions of signalling pathway genes in clonal B-cell lymphocytosis with marginal zone features. Br. J. Haematol. 167:718–20
    [Google Scholar]
  10. Busman-Sahay K, Drake L, Sitaram A, Marks M, Drake JR 2013. Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs. PLOS ONE 8:e54938
    [Google Scholar]
  11. Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F et al. 2013. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Investig. 123:5009–22
    [Google Scholar]
  12. Calado DP, Zhang B, Srinivasan L, Sasaki Y, Seagal J et al. 2010. Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell 18:580–89
    [Google Scholar]
  13. Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H et al. 2016. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J. Clin. Investig. 126:3351–62
    [Google Scholar]
  14. Cattoretti G, Mandelbaum J, Lee N, Chaves AH, Mahler AM et al. 2009. Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation. Cancer Res 69:8686–92
    [Google Scholar]
  15. Cerhan JR, Berndt SI, Vijai J, Ghesquieres H, McKay J et al. 2014. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat. Genet. 46:1233–38
    [Google Scholar]
  16. Ceribelli M, Kelly PN, Shaffer AL, Wright GW, Xiao W et al. 2014. Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. PNAS 111:11365–70
    [Google Scholar]
  17. Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G et al. 2011. Combined genetic inactivation of β2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20:728–40
    [Google Scholar]
  18. Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG et al. 2013. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24:777–90
    [Google Scholar]
  19. Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP et al. 2016. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869–81
    [Google Scholar]
  20. Chen L, Monti S, Juszczynski P, Ouyang J, Chapuy B et al. 2013. SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer Cell 23:826–38
    [Google Scholar]
  21. Cheng S, Coffey G, Zhang XH, Shaknovich R, Song Z et al. 2011. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood 118:6342–52
    [Google Scholar]
  22. Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M et al. 2009. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459:717–21
    [Google Scholar]
  23. Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL et al. 1998. Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8:497–508
    [Google Scholar]
  24. Czuczman MS, Trneny M, Davies A, Rule SA, Linton K et al. 2017. A phase 2/3 multicenter, randomized, open-label study of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin. Cancer Res. 23:4127–37
    [Google Scholar]
  25. Davis RE, Brown KD, Siebenlist U, Staudt LM 2001. Constitutive nuclear factor κB activity is required for survival of activated B cell–like diffuse large B cell lymphoma cells. J. Exp. Med. 194:1861–74
    [Google Scholar]
  26. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM et al. 2010. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–92
    [Google Scholar]
  27. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM 1997. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276:589–92
    [Google Scholar]
  28. Dragone LL, Myers MD, White C, Gadwal S, Sosinowski T et al. 2006. Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner. PNAS 103:18202–7
    [Google Scholar]
  29. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF 1995. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3:39–50
    [Google Scholar]
  30. Ferch U, Kloo B, Gewies A, Pfander V, Duwel M et al. 2009. Inhibition of MALT1 protease activity is selectively toxic for activated B cell–like diffuse large B cell lymphoma cells. J. Exp. Med. 206:2313–20
    [Google Scholar]
  31. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB et al. 2010. Selective inhibition of BET bromodomains. Nature 468:1067–73
    [Google Scholar]
  32. Flossbach L, Antoneag E, Buck M, Siebert R, Mattfeldt T et al. 2011. BCL6 gene rearrangement and protein expression are associated with large cell presentation of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Int. J. Cancer 129:70–77
    [Google Scholar]
  33. Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E et al. 2016. Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol 131:865–75
    [Google Scholar]
  34. Ganapathi KA, Jobanputra V, Iwamoto F, Jain P, Chen J et al. 2016. The genetic landscape of dural marginal zone lymphomas. Oncotarget 7:43052–61
    [Google Scholar]
  35. Garcia-Ramirez I, Tadros S, Gonzalez-Herrero I, Martin-Lorenzo A, Rodriguez-Hernandez G et al. 2017. Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice. Blood 129:2645–56
    [Google Scholar]
  36. Green JA, Suzuki K, Cho B, Willison LD, Palmer D et al. 2011. The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement. Nat. Immunol. 12:672–80
    [Google Scholar]
  37. Green MR, Kihira S, Liu CL, Nair RV, Salari R et al. 2015. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. PNAS 112:E1116–25
    [Google Scholar]
  38. Grommes C, Pastore A, Palaskas N, Tang SS, Campos C et al. 2017. Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov 7:1018–29
    [Google Scholar]
  39. Gross AJ, Lyandres JR, Panigrahi AK, Prak ET, DeFranco AL 2009. Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J. Immunol. 182:5382–92
    [Google Scholar]
  40. Grossman RL, Heath AP, Ferretti V, Varmus HE, Lowy DR et al. 2016. Toward a shared vision for cancer genomic data. N. Engl. J. Med. 375:1109–12
    [Google Scholar]
  41. Hailfinger S, Lenz G, Ngo V, Posvitz-Fejfar A, Rebeaud F et al. 2009. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. PNAS 106:19946–51
    [Google Scholar]
  42. Hashwah H, Schmid CA, Kasser S, Bertram K, Stelling A et al. 2017. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. PNAS 114:9701–6
    [Google Scholar]
  43. Havranek O, Xu J, Kohrer S, Wang Z, Becker L et al. 2017. Tonic B-cell receptor signaling in diffuse large B-cell lymphoma. Blood 130:995–1006
    [Google Scholar]
  44. Healy JA, Nugent A, Rempel RE, Moffitt AB, Davis NS et al. 2016. GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. Blood 127:2723–31
    [Google Scholar]
  45. Heise N, De Silva NS, Silva K, Carette A, Simonetti G et al. 2014. Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J. Exp. Med. 211:2103–18
    [Google Scholar]
  46. Hodson DJ, Shaffer AL, Xiao W, Wright GW, Schmitz R et al. 2016. Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2. PNAS 113:E2039–46
    [Google Scholar]
  47. Iqbal J, Greiner TC, Patel K, Dave BJ, Smith L et al. 2007. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 21:2332–43
    [Google Scholar]
  48. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K 2005. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19:523–34
    [Google Scholar]
  49. Jiang Y, Ortega-Molina A, Geng H, Ying HY, Hatzi K et al. 2017. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov 7:38–53
    [Google Scholar]
  50. Johansson P, Klein-Hitpass L, Grabellus F, Arnold G, Klapper W et al. 2016. Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas. Oncotarget 7:62627–39
    [Google Scholar]
  51. Kagan JC, Magupalli VG, Wu H 2014. SMOCs: supramolecular organizing centres that control innate immunity. Nat. Rev. Immunol. 14:821–26
    [Google Scholar]
  52. Kelly PN, Romero DL, Yang Y, Shaffer AL, Chaudhary D et al. 2015. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J. Exp. Med. 212:2189–201
    [Google Scholar]
  53. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG et al. 2012. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J. Exp. Med. 209:1553–65
    [Google Scholar]
  54. Klein U, Casola S, Cattoretti G, Shen Q, Lia M et al. 2006. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7:773–82
    [Google Scholar]
  55. Kloo B, Nagel D, Pfeifer M, Grau M, Duwel M et al. 2011. Critical role of PI3K signaling for NF-κB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. PNAS 108:272–77
    [Google Scholar]
  56. Kraan W, Horlings HM, van Keimpema M, Schilder-Tol EJ, Oud ME et al. 2013. High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immune-privileged sites. Blood Cancer J 3:e139
    [Google Scholar]
  57. Kraus M, Pao LI, Reichlin A, Hu Y, Canono B et al. 2001. Interference with immunoglobulin (Ig)α immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B cell development, depending on the availability of an Igβ cytoplasmic tail. J. Exp. Med. 194:455–69
    [Google Scholar]
  58. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5
    [Google Scholar]
  59. Kuroda K, Han H, Tani S, Tanigaki K, Tun T et al. 2003. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18:301–12
    [Google Scholar]
  60. Lam KP, Kuhn R, Rajewsky K 1997. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073–83
    [Google Scholar]
  61. Lam LT, Davis RE, Pierce J, Hepperle M, Xu Y et al. 2005. Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11:28–40
    [Google Scholar]
  62. Lam LT, Wright G, Davis RE, Lenz G, Farinha P et al. 2008. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma. Blood 111:3701–13
    [Google Scholar]
  63. Lenz G, Davis RE, Ngo VN, Lam L, George TC et al. 2008.a Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319:1676–79
    [Google Scholar]
  64. Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W et al. 2007. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med. 204:633–43
    [Google Scholar]
  65. Lenz G, Wright G, Dave SS, Xiao W, Powell J et al. 2008.b Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359:2313–23
    [Google Scholar]
  66. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS et al. 2008.c Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. PNAS 105:13520–25
    [Google Scholar]
  67. Lin SC, Lo YC, Wu H 2010. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature 465:885–90
    [Google Scholar]
  68. Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA et al. 2017. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 31:833–43.e5
    [Google Scholar]
  69. Losing M, Goldbeck I, Manno B, Oellerich T, Schnyder T et al. 2013. The Dok-3/Grb2 protein signal module attenuates Lyn kinase-dependent activation of Syk kinase in B cell antigen receptor microclusters. J. Biol. Chem. 288:2303–13
    [Google Scholar]
  70. Lossos IS, Alizadeh AA, Eisen MB, Chan WC, Brown PO et al. 2000. Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. PNAS 97:10209–13
    [Google Scholar]
  71. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9
    [Google Scholar]
  72. Maecker HT, Levy S 1997. Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J. Exp. Med. 185:1505–10
    [Google Scholar]
  73. Mareschal S, Pham-Ledard A, Viailly PJ, Dubois S, Bertrand P et al. 2017. Identification of somatic mutations in primary cutaneous diffuse large B-cell lymphoma, leg type by massive parallel sequencing. J. Investig. Dermatol. 137:1984–94
    [Google Scholar]
  74. Martinez N, Almaraz C, Vaque JP, Varela I, Derdak S et al. 2014. Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation. Leukemia 28:1334–40
    [Google Scholar]
  75. Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM et al. 2014. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell–like diffuse large B-cell lymphoma cells. PNAS 111:2349–54
    [Google Scholar]
  76. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C et al. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–12
    [Google Scholar]
  77. Mecklenbrauker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A 2002. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416:860–65
    [Google Scholar]
  78. Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M 2011. Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 122:791–92
    [Google Scholar]
  79. Montesinos-Rongen M, Purschke F, Kuppers R, Deckert M 2014. Immunoglobulin repertoire of primary lymphomas of the central nervous system. J. Neuropathol. Exp. Neurol. 73:1116–25
    [Google Scholar]
  80. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J et al. 2010. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42:181–85
    [Google Scholar]
  81. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL et al. 2011. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476:298–303
    [Google Scholar]
  82. Muppidi JR, Schmitz R, Green JA, Xiao W, Larsen AB et al. 2014. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 516:254–58
    [Google Scholar]
  83. Nakamura T, Tateishi K, Niwa T, Matsushita Y, Tamura K et al. 2015. Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol. Appl. Neurobiol. 42:279–90
    [Google Scholar]
  84. Naylor TL, Tang H, Ratsch BA, Enns A, Loo A et al. 2011. Protein kinase C inhibitor Sotrastaurin selectively inhibits the growth of CD79-mutant diffuse large B-cell lymphomas. Cancer Res 71:2643–53
    [Google Scholar]
  85. Ngo VN, Davis RE, Lamy L, Yu X, Zhao H et al. 2006. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441:106–10
    [Google Scholar]
  86. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W et al. 2011. Oncogenically active MYD88 mutations in human lymphoma. Nature 470:115–19
    [Google Scholar]
  87. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S et al. 2010. Suppression of inflammation by a synthetic histone mimic. Nature 468:1119–23
    [Google Scholar]
  88. Nowakowski GS, Chiappella A, Witzig TE, Spina M, Gascoyne RD et al. 2016. ROBUST: lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncol 12:1553–63
    [Google Scholar]
  89. Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y et al. 2015. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat. Med. 21:1199–208
    [Google Scholar]
  90. Ouchida R, Kurosaki T, Wang JY 2010. A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface B cell receptor levels and B cell activation. J. Immunol. 185:294–301
    [Google Scholar]
  91. Parry M, Rose-Zerilli MJ, Gibson J, Ennis S, Walewska R et al. 2013. Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLOS ONE 8:e83244
    [Google Scholar]
  92. Parry M, Rose-Zerilli MJ, Ljungstrom V, Gibson J, Wang J et al. 2015. Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing. Clin. Cancer Res. 21:4174–83
    [Google Scholar]
  93. Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P et al. 2008. AID is required for germinal center-derived lymphomagenesis. Nat. Genet. 40:108–12
    [Google Scholar]
  94. Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A et al. 2006. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203:311–17
    [Google Scholar]
  95. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D et al. 2011. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43:830–37
    [Google Scholar]
  96. Paul J, Soujon M, Wengner AM, Zitzmann-Kolbe S, Sturz A et al. 2017. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking bcr-dependent and -independent activation of NF-κB and AKT. Cancer Cell 31:64–78
    [Google Scholar]
  97. Pfeifer M, Grau M, Lenze D, Wenzel SS, Wolf A et al. 2013. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. PNAS 110:12420–25
    [Google Scholar]
  98. Phelan JD, Young RM, Webster DE, Roulland S, Wright GW et al. 2018. A multiprotein supercomplex controlling oncogenic signaling in lymphoma. Nature 560:387–91
    [Google Scholar]
  99. Pongas GN, Annunziata CM, Staudt LM 2017. PI3Kδ inhibition causes feedback activation of PI3Kα in the ABC subtype of diffuse large B-cell lymphoma. Oncotarget 8:81794–802
    [Google Scholar]
  100. Qiao Q, Yang C, Zheng C, Fontan L, David L et al. 2013. Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. Mol. Cell 51:766–79
    [Google Scholar]
  101. Read JA, Koff JL, Nastoupil LJ, Williams JN, Cohen JB, Flowers CR 2014. Evaluating cell-of-origin subtype methods for predicting diffuse large B-cell lymphoma survival: a meta-analysis of gene expression profiling and immunohistochemistry algorithms. Clin. Lymphoma Myeloma Leuk. 14:460–67.e2
    [Google Scholar]
  102. Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL et al. 2017. Genetic and functional drivers of diffuse large B cell lymphoma. Cell 171:481–94.e15
    [Google Scholar]
  103. Rickert RC, Rajewsky K, Roes J 1995. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376:352–55
    [Google Scholar]
  104. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E et al. 2002. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346:1937–47
    [Google Scholar]
  105. Rui L, Drennan AC, Ceribelli M, Zhu F, Wright GW et al. 2016. Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma. PNAS 113:E7260–67
    [Google Scholar]
  106. Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T et al. 2003. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18:675–85
    [Google Scholar]
  107. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303
    [Google Scholar]
  108. Sander S, Chu VT, Yasuda T, Franklin A, Graf R et al. 2015. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43:1075–86
    [Google Scholar]
  109. Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM 2014. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb. Perspect. Med. 4:a014282
    [Google Scholar]
  110. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD et al. 2018. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 378:1396–407
    [Google Scholar]
  111. Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W et al. 2012. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490:116–20
    [Google Scholar]
  112. Schrader AMR, Jansen PM, Willemze R, Vermeer MH, Cleton-Jansen AM et al. 2018. High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma. Blood 131:2086–89
    [Google Scholar]
  113. Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H 2006. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25:225–36
    [Google Scholar]
  114. Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W et al. 2014. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123:1214–17
    [Google Scholar]
  115. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM 2000. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199–212
    [Google Scholar]
  116. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM et al. 2010. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. PNAS 107:20980–85
    [Google Scholar]
  117. Spina V, Khiabanian H, Messina M, Monti S, Cascione L et al. 2016. The genetics of nodal marginal zone lymphoma. Blood 128:1362–73
    [Google Scholar]
  118. Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH et al. 2009. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139:573–86
    [Google Scholar]
  119. Taniguchi K, Takata K, Chuang SS, Miyata-Takata T, Sato Y et al. 2016. Frequent MYD88 L265P and CD79B mutations in primary breast diffuse large B-cell lymphoma. Am. J. Surg. Pathol. 40:324–34
    [Google Scholar]
  120. Thome M, Charton JE, Pelzer C, Hailfinger S 2010. Antigen receptor signaling to NF-κB via CARMA1, BCL10, and MALT1. Cold Spring Harb. Perspect. Biol. 2:a003004
    [Google Scholar]
  121. Treon SP, Tripsas CK, Meid K, Warren D, Varma G et al. 2015. Ibrutinib in previously treated Waldenström's macroglobulinemia. N. Engl. J. Med. 372:1430–40
    [Google Scholar]
  122. Treon SP, Xu L, Yang G, Zhou Y, Liu X et al. 2012. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N. Engl. J. Med. 367:826–33
    [Google Scholar]
  123. Valls E, Lobry C, Geng H, Wang L, Cardenas M et al. 2017. BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells. Cancer Discov 7:506–21
    [Google Scholar]
  124. Vater I, Montesinos-Rongen M, Schlesner M, Haake A, Purschke F et al. 2015. The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia 29:677–85
    [Google Scholar]
  125. Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC 2012. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120:2240–48
    [Google Scholar]
  126. Wang X, Li JP, Kuo HK, Chiu LL, Dement GA et al. 2012. Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK). J. Biol. Chem. 287:11037–48
    [Google Scholar]
  127. Wang Y, Brooks SR, Li X, Anzelon AN, Rickert RC, Carter RH 2002. The physiologic role of CD19 cytoplasmic tyrosines. Immunity 17:501–14
    [Google Scholar]
  128. Wheeler ML, Dong MB, Brink R, Zhong XP, DeFranco AL 2013. Diacylglycerol kinase ζ limits B cell antigen receptor–dependent activation of ERK signaling to inhibit early antibody responses. Sci. Signal. 6:ra91
    [Google Scholar]
  129. Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S et al. 2015. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat. Med. 21:922–26
    [Google Scholar]
  130. Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM 2003. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. PNAS 100:9991–96
    [Google Scholar]
  131. Yamada S, Ishida Y, Matsuno A, Yamazaki K 2015. Primary diffuse large B-cell lymphomas of central nervous system exhibit remarkably high prevalence of oncogenic MYD88 and CD79B mutations. Leuk. Lymphoma 56:2141–45
    [Google Scholar]
  132. Yang Y, Kelly P, Shaffer AL, Schmitz R, Yoo HM et al. 2016. Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B cell lymphoma. Cancer Cell 29:494–507
    [Google Scholar]
  133. Yang Y, Schmitz R, Mitala J, Whiting A, Xiao W et al. 2014. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discov 4:480–93
    [Google Scholar]
  134. Yang Y, Shaffer AL, Emre NC, Ceribelli M, Zhang M et al. 2012. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21:723–37
    [Google Scholar]
  135. Yarkoni Y, Getahun A, Cambier JC 2010. Molecular underpinning of B-cell anergy. Immunol. Rev. 237:249–63
    [Google Scholar]
  136. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N et al. 1997. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat. Genet. 16:161–70
    [Google Scholar]
  137. Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K et al. 1993. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262:747–50
    [Google Scholar]
  138. Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Hussein S et al. 2013. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat. Immunol. 14:1084–92
    [Google Scholar]
  139. Young RM, Staudt LM 2013. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat. Rev. Drug Discov. 12:229–43
    [Google Scholar]
  140. Young RM, Wu T, Schmitz R, Dawood M, Xiao W et al. 2015. Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. PNAS 112:13447–54
    [Google Scholar]
  141. Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB et al. 2015. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat. Med. 21:1190–98
    [Google Scholar]
  142. Zhang J, Vlasevska S, Wells VA, Nataraj S, Holmes AB et al. 2017. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov 7:322–37
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030518-055734
Loading
/content/journals/10.1146/annurev-cancerbio-030518-055734
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error