The genetic basis of diffuse large B-cell lymphoma

Current Opinion in Hematology

Volumn 20, Issue 4, 2013, Pages 336-344

  Pasqualucci, Laura ^a  

^a NewYork Presbyterian Hospital   (United States)

Author keywords

Diffuse large B cell lymphoma; Epigenetic modifiers; Genomic analysis; Germinal center; Immune escape

Indexed keywords

ACYLTRANSFERASE; B LYMPHOCYTE RECEPTOR; BETA 2 MICROGLOBULIN; BREAKPOINT CLUSTER REGION PROTEIN; CD40 LIGAND; CD79A ANTIGEN; CD79B ANTIGEN; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; DNA; E1A ASSOCIATED P300 PROTEIN; GLUTATHIONE; HISTONE ACETYLTRANSFERASE; HISTONE H3; HISTONE METHYLTRANSFERASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; JANUS KINASE; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 3; MITOGEN ACTIVATED PROTEIN KINASE; MIXED LINEAGE LEUKEMIA 2 PROTEIN; MIXED LINEAGE LEUKEMIA PROTEIN; MYELOID DIFFERENTIATION FACTOR 88; PHOSPHATIDYLINOSITOL 3 KINASE; PROGRAMMED DEATH 1 LIGAND 1; PROTEIN BCL 2; PROTEIN BCL 6; PROTEIN P53; SHORT HAIRPIN RNA; STAT3 PROTEIN; TRANSCRIPTION FACTOR EZH2; UNCLASSIFIED DRUG; UNINDEXED DRUG;

APOPTOSIS; B LYMPHOCYTE; CANCER DIAGNOSIS; CANCER GENETICS; CANCER PATIENT; CANCER RESISTANCE; CELL CYCLE ARREST; CELL CYCLE REGULATION; CELL DIFFERENTIATION; CELL TRANSFORMATION; CHROMATIN STRUCTURE; DNA DAMAGE; EPIGENETICS; FATTY ACID OXIDATION; FOLLICULAR LYMPHOMA; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENE IDENTIFICATION; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC HETEROGENEITY; GENOME; GERMINAL CENTER; HEREDITY; HISTONE METHYLATION; HISTOPATHOLOGY; HUMAN; IN VITRO STUDY; LARGE CELL LYMPHOMA; MOLECULAR BIOLOGY; MOLECULAR PATHOLOGY; MOLECULAR RECOGNITION; MOLECULARLY TARGETED THERAPY; NATURAL KILLER CELL; OXIDATIVE PHOSPHORYLATION; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR GROWTH;

CELL TRANSFORMATION, NEOPLASTIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GENETIC VARIATION; HUMANS; IMMUNITY, CELLULAR; LYMPHOMA, LARGE B-CELL, DIFFUSE;

EID: 84880202725     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e3283623d7f     Document Type: Review

References (64)

1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer (IARC); 2008.
2. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503-511.
3. Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol 2012; 30:565-610.
4. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8:22-33.
5. Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105:1851-1861.
6. Polo JM, Dell'Oso T, Ranuncolo SM, et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med 2004; 10:1329-1335.
7. Polo JM, Juszczynski P, Monti S, et al. Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas. Proc Natl Acad Sci USA 2007; 104:3207-3212.
8. Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 2008; 111:2230-2237.
9. Caro P, Kishan AU, Norberg E, et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 2012; 22:547-560. This elegant work characterizes a metabolic signature in the previously defined Ox/ Phos subgroup of DLBCL, which may have therapeutic implications because perturbation of the fatty acid oxidation program and glutathione synthesis proved to be selectively toxic in this DLBCL subset.
10. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA 2012; 109:3879-3884
11. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histonemodifying genes in non-Hodgkin lymphoma. Nature 2011; 476:298-303. The first analysis of the DLBCL coding genome using whole-exome/whole-transcriptome sequencing technologies; this study also revealed MLL2 as the most common target of somatic mutations in DLBCL (40% of cases) and follicular lymphoma (89% of cases).
12. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011; 43:830-837.
13. Scott DW, Mungall KL, Ben-Neriah S, et al. TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. Blood 2012; 119:4949-4952. The first novel gene fusion identified to date in DLBCL through RNA-sequencing.
14. Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 2001; 412: 341-346.
15. Jiang Y, Soong TD, Wang L, et al. Genome-wide detection of genes targeted by non-Ig somatic hypermutation in lymphoma. PLoS One 2012; 7:e40332. This is the only study to interrogate DLBCL patients and cell lines for the presence of mutations in regulatory sequences genome-wide, leading to the identification of aberrant SHM hotspots and providing initial evidence for their functional effect in altering gene transcription of the target gene.
16. Monti S, Chapuy B, Takeyama K, et al. Integrative analysis reveals an outcome- associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell 2012; 22:359-372.
17. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev 2000; 14:1553-1577.
18. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature 1996; 384:641-643.
19. Ogryzko VV, Schiltz RL, Russanova V, et al. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 1996; 87:953-959.
20. Gu W, Shi XL, Roeder RG. Synergistic activation of transcription by CBP and p53. Nature 1997; 387:819-823.
21. Lill NL, Grossman SR, Ginsberg D, et al. Binding and modulation of p53 by p300/CBP coactivators. Nature 1997; 387:823-827.
22. Avantaggiati ML, Ogryzko V, Gardner K, et al. Recruitment of p300/CBP in p53-dependent signal pathways. Cell 1997; 89:1175-1184.
23. Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 2002; 32:606-613.
24. Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011; 471:189-195. The first demonstration that CREBBP is targeted by loss-of-function genetic lesions in nearly 30% of DLBCL patients; this study also documents that CREBBP mutations impair the acetylation of BCL6 and p53, providing one mechanism by which these lesions may contribute to lymphomagenesis.
25. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 2004; 432:635-639.
26. Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 1995; 376:348-351.
27. Cerchietti LC, Hatzi K, Caldas-Lopes E, et al. BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest 2010. [Epub ahead of print].
28. Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 2012; 81:65-95. Comprehensive overview discussing the role of histone H3K4 methyltransferases as a mark of active transcription, enhancer signatures, and developmentally poised genes.
29. Herz HM, Mohan M, Garruss AS, et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev 2012; 26:2604-2620. Reports a previously unrecognized function for Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes as a major H3K4 monomethyltransferase on enhancers in vivo, implying a central role in the transition from inactive/ poised to active enhancers.
30. Kanda H, Nguyen A, Chen L, et al. The Drosophila ortholog of MLL 3/MLL 4, trithorax related, functions as a negative regulator of tissue growth. Mol Cell Biol 2013; 33:1702-1710
31. Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USAm 2013; 110:1398-1403.
32. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42:181-185.
33. Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011; 470:115-119.
34. Sneeringer CJ, Scott MP, Kuntz KW, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA 2010; 107:20980-20985.
35. Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 2012; 8:890-896.
36. Together with [36 ] and [37 ], this study represents the original report on the development of a potent, selective inhibitor of EZH2, demonstrating its efficacy in animal models and paving the way to a phase I clinical trial in DLBCL patients with EZH2 mutations. 36. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492:108-112. See [35 ].
37. Qi W, Chan H, Teng L, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci USA 2012; 109:21360-21365. See [35 ].
38. Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011; 20:728-740
39. Moingeon P, Chang HC, Wallner BP, et al. CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature 1989; 339:312-314.
40. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011; 471:377-381.
41. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 2010; 18:590-605.
42. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116:3268-3277.
43. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001; 194:1861-1874.
44. Lam KP, Kuhn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 1997; 90:1073-1083.
45. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88-92.
46. Yang Y, Shaffer AL 3rd, Emre NC, et al. Exploiting synthetic lethality for the therapy ofABCdiffuse largeBcell lymphoma. Cancer Cell2012; 21:723-737
47. Fontan L, Yang C, Kabaleeswaran V, et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 2012; 22:812-824. Through the development of a method for generating active paracaspases in vitro, this study identifies a potent and irreversible inhibitor of MALT1 that suppresses NF-kB activity in vitro and in xenotransplanted ABC-DLBCL tumors with minimal toxicity.
48. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115-119.
49. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009; 459:717-721.
50. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712-716.
51. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319:1676-1679.
52. Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev 2012; 247:172-183.
53. Migliazza A, Martinotti S, Chen W, et al. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci USA 1995; 92:12520-12524.
54. Pasqualucci L, Migliazza A, Fracchiolla N, et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA 1998; 95:11816-11821.
55. Shen HM, Peters A, Baron B, et al. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 1998; 280:1750-1752.
56. Wang X, Li Z, Naganuma A, Ye BH. Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci USA 2002; 99:15018-15023.
57. Pasqualucci L, Migliazza A, Basso K, et al. Mutations of the BCL6 protooncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 2003; 101:2914-2923.
58. Duan S, Cermak L, Pagan JK, et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 2012; 481: 90-93. Two important findings for normal GC B-cell biology and lymphomagenesis are as follows: first, a novel mechanism for the regulation of BCL6 protein stability by the FBXO11 ubiquitin ligase; and second, the presence of mutations targeting FBXO11 in approximately 5% of DLBCL patients, adding to the list of genetic lesions perturbing BCL6 activity in lymphoma.
59. Ying CY, Dominguez-Sola D, Fabi M, et al. MEF2B Mutations lead to deregulated expression of the BCL6 oncogene in diffuse large B-cell lymphoma and follicular lymphoma [abstract]. Blood (ASH Annual Meeting Abstracts) 2012; 120:abstr. 1284.
60. Cattoretti G, Pasqualucci L, Ballon G, et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 2005; 7:445-455.
61. Cerchietti LC, Ghetu AF, Zhu X, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 2010; 17:400-411.
62. Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and preplasma memory B cells. Immunity 2003; 19:607-620.
63. Mandelbaum J, Bhagat G, Tang H, et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell 2010; 18:568-579.
64. Pasqualucci L, Compagno M, Houldsworth J, et al. Inactivation of the PRDM1/ BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med 2006; 203: 311-317.