Novel Findings in Follicular Lymphoma Pathogenesis and the Concepts of Targeted Therapy


Authors: J. Deván 1;  K. Musilová 1;  A. Janíková 1,2;  M. Mráz 1,2
Authors‘ workplace: CEITEC – Středoevropský technologický institut, MU, Brno 1;  Interní hematologická a onkologická klinika LF MU a FN Brno 2
Published in: Klin Onkol 2017; 30(4): 247-257
Category: Review
doi: 10.14735/amko2017247

Overview

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed by the discovery of BCL2 translocations to the region encoding the immunoglobulin heavy chain, which accompany the vast majority of cases. This aberration leads to the ectopic and constitutive expression of anti-apoptotic BCL2 protein in B-cells. Nevertheless, the aberration alone is not sufficient for FL development, which suggests necessity of further genetic aberrations acquisition for neoplastic transformation to FL. Their discovery has been enabled by recent progress in the field of massive parallel sequencing (next generation sequencing), which revealed high number of genetic aberrations connected with onset and progression of FL. The occurrence of many of these aberrations in the early stages of the disease, and the fact that they are shared by the majority of patients with FL, fundamentally changed our former understanding of the disease onset. Furthermore, in a large fraction of patients, FL undergoes histological transformation to a more aggressive lymphoma, which is also associated with specific genetic alterations. In this review, we summarize the current knowledge of molecular pathways connected with FL biology and discuss their role in the context of normal B-cell development. Understanding of FL biology is essential for the development of new targeted therapies and the stratification of patients, and potentially also for the selection of treatment for specific patients who share the same genetic aberrations.

Key words:
follicular lymphoma – mutation – aberration – apoptosis – epigenetic regulators – microRNA

This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustain ability Programme II.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
28. 1. 2017

Accepted:
5. 3. 2017


Sources

1. Smith A, Crouch S, Lax S et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer 2015; 112 (9): 1575–1584. doi: 10.1038/bjc.2015.94.

2. Tsujimoto Y, Cossman J, Jaffe E et al. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228 (4706): 1440–1443.

3. Tsujimoto Y, Gorham J, Cossman J et al. The t (14; 18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 1985; 229 (4720): 1390–1393.

4. Casulo C, Byrtek M, Dawson KL et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone De-fines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol 2015; 33 (23): 2516–2522. doi: 10.1200/JCO.2014.59.7534.

5. Pastore A, Jurinovic V, Kridel R et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 2015; 16 (9): 1111–1122. doi: 10.1016/S1470-2045 (15) 00169-2.

6. Jurinovic V, Kridel R, Staiger AM et al. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood 2016; 128 (8): 1112–1120. doi: 10.1182/blood-2016-05-717355.

7. Liu Y, Hernandez AM, Shibata D et al. BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci U S A 1994; 91 (19): 8910–8914.

8. McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t (14; 18). Nature 1991; 349 (6306): 254–256.

9. Roulland S, Kelly RS, Morgado E et al. t (14; 18) Translocation: a predictive blood biomarker for follicular lymphoma. J Clin Oncol 2014; 32 (13): 1347–1355. doi: 10.1200/JCO.2013.52.8190.

10. Cong P, Raffeld M, Teruya-Feldstein J et al. In situ localization of follicular lymphoma: description and analysis by laser capture microdissection. Blood 2002; 99 (9): 3376–3382.

11. Janíková A, Michalka J, Tichý B et al. Folikulární lymfom a význam nádorového mikroprostředí. Transfuze Hematol Dnes 2010; 16 (3): 150–157.

12. Mraz M, Zent CS, Church AK et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol 2011; 155 (1): 53–64. doi: 10.1111/j.13652141.2011.08794.x.

13. Labidi SI, Ménétrier-Caux C, Chabaud S et al. Serum cytokines in follicular lymphoma. Correlation of TGF-β and VEGF with survival. Ann Hematol 2010; 89 (1): 25–33. doi: 10.1007/s00277-009-0777-8.

14. Okosun J, Bödör C, Wang J et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014; 46 (2): 176–181. doi: 10.1038/ng.2856.

15. Bouska A, McKeithan TW, Deffenbacher KE et al. Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma. Blood 2014; 123 (11): 1681–1690. doi: 10.1182/blood-2013-05-500595.

16. Pasqualucci L, Khiabanian H, Fangazio M et al. Genetics of follicular lymphoma transformation. Cell Rep 2014; 6 (1): 130–140. doi: 10.1016/j.celrep.2013.12.027.

17. Okosun J, Wolfson RL, Wang J et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet 2016; 48 (2): 183–188. doi: 10.1038/ng.3473.

18. Thompson MA, Edmonds MD, Liang S et al. miR-31 and miR-17-5p levels change during transformation of follicular lymphoma. Hum Pathol 2016; 50: 118–126. doi: 10.1016/j.humpath.2015.11.011.

19. Dave SS, Wright G, Tan B et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351 (21): 2159–2169.

20. Oricchio E, Nanjangud G, Wolfe AL et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 2011; 147 (3): 554–564. doi: 10.1016/j.cell. 2011.09.035.

21. Huang X, Shen Y, Liu M et al. Quantitative proteomics reveals that miR-155 regulates the PI3K-AKT pathway in diffuse large B-cell lymphoma. Am J Pathol 2012; 181 (1): 26–33. doi: 10.1016/j.ajpath.2012.03.013.

22. Karube K, Martínez D, Royo C et al. Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours. J Pathol 2014; 234 (3): 423–430. doi: 10.1002/path.4428.

23. Calvo KR, Dabir B, Kovach A et al. IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma. Blood 2008; 112 (9): 3818–3826. doi: 10.1182/blood-2008-02-138933.

24. Yildiz M, Li H, Bernard D et al. Activating STAT6 mutations in follicular lymphoma. Blood 2015; 125 (4): 668–679. doi: 10.1182/blood-2014-06-582650.

25. Mottok A, Renné C, Seifert M et al. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood 2009; 114 (20): 4503–4506. doi: 10.1182/blood-2009-06-225839.

26. Maffei R, Fiorcari S, Martinelli S et al. Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib. J Hematol Oncol 2015; 8: 60. doi: 10.1186/s13045-015-0157-x.

27. Mráz M, Doubek M, Mayer J. Inhibition of B Cell Receptor Signaling: a First Targeted Therapeutic Approach for Chronic Lymphocytic Leukemia and Other B Cell Lymphomas. Klin Onkol 2013; 26 (3): 179–185.

28. Pasqualucci L, Migliazza A, Basso K et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 2003; 101 (8): 2914–2923.

29. Correia C, Schneider PA, Dai H et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood 2015; 125 (4): 658–667. doi: 10.1182/blood-2014-04-571786.

30. Béguelin W, Popovic R, Teater M et al. EZH2 is re-quired for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013; 23 (5): 677–692. doi: 10.1016/j.ccr.2013.04.011.

31. Klein U, Tu Y, Stolovitzky GA et al. Transcriptional analysis of the B cell germinal center reaction. Proc Natl Acad Sci U S A 2003; 100 (5): 2639–2644.

32. Pérez-Roger I, Solomon DL, Sewing A et al. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27 (Kip1) binding to newly formed complexes. Oncogene 1997; 14 (20): 2373–2381.

33. Rao DS, O’Connell RM, Chaudhuri AA et al. MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity 2010; 33 (1): 48–59. doi: 10.1016/j.immuni.2010.06.013.

34. Mraz M, Chen L, Rassenti LZ et al. miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood 2014; 124 (1): 84–95. doi: 10.1182/blood-2013-09-527234.

35. O’Donnell KA, Wentzel EA, Zeller KI et al. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435 (7043): 839–843.

36. Li Y, Choi PS, Casey SC et al. MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation and a Neoplastic State. Cancer Cell 2014; 26 (2): 262–272. doi: 10.1016/j.ccr.2014.06.014.

37. Šmardová J, Moulis M, Lišková K et al. Double-hit lymphomas – review of the literature and case report. Klin Onkol 2014; 27 (1): 24–32. doi: 10.14735/amko201424.

38. Maniati E, Marzec J, Okosun J et al. Investigating the role of MLL2 (Mll4) in B cell development. Blood 2013; 122 (21): 343–343.

39. Berg T, Thoene S, Yap D et al. A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. Blood 2014; 123 (25): 3914–3924. doi: 10.1182/blood-2012-12-473439.

40. Guo S, Chan JK, Iqbal J et al. EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. Clin Cancer Res 2014; 20 (12): 3078–3086. doi: 10.1158/1078-0432.CCR-13-1597.

41. Lu C, Han HD, Mangala LS et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell 2010; 18 (2): 185–197. doi: 10.1016/j.ccr.2010.06.016.

42. 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 (11): 890–896. doi: 10.1038/nchembio.1084.

43. McCabe MT, Ott HM, Ganji G et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492 (7427): 108–112. doi: 10.1038/nature11606.

44. Pasqualucci L, Dominguez-Sola D, Chiarenza A et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011; 471 (7337): 189–195. doi: 10.1038/nature09730.

45. Fontes JD, Kanazawa S, Jean D et al. Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. Mol Cell Biol 1999; 19 (1): 941–947.

46. Kretsovali A, Agalioti T, Spilianakis C et al. Involvement of CREB binding protein in expression of major histocompatibility complex class II genes via interaction with the class II transactivator. Mol Cell Biol 1998; 18 (11): 6777–6783.

47. Green MR, Kihira S, Liu CL et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A 2015; 112 (10): E1116–E1125. doi: 10.1073/pnas.1501199112.

48. Pasini D, Malatesta M, Jung HR et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res 2010; 38 (15): 4958–4969. doi: 10.1093/nar/gkq 244.

49. Han A, He J, Wu Y et al. Mechanism of recruitment of class II histone deacetylases by myocyte enhancer factor-2. J Mol Biol 2005; 345 (1): 91–102.

50. Morin RD, Mendez-Lago M, Mungall AJ et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476 (7360): 298–303. doi: 10.1038/nature10351.

51. Ying CY, Dominguez-Sola D, Fabi M et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 2013; 14 (10): 1084–1092. doi: 10.1038/ni.2688.

52. Li H, Kaminski MS, Li Y et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood 2014; 123 (10): 1487–1498. doi: 10.1182/blood-2013-05-500264.

53. Morschhauser F, Terriou L, Coiffier B et al. Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia. Invest New Drugs 2015; 33 (2): 423–431. doi: 10.1007/s10637-015-0206-x.

54. Chen R, Frankel P, Popplewell L et al. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica 2015; 100 (3): 357–362. doi: 10.3324/haematol.2014.117473.

55. Westin JR, Chu F, Zhang M et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 2014; 15 (1): 69–77. doi: 10.1016/S1470-2045 (13) 70551-5.

56. Leonard JP, Jung SH, Johnson J et al. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol 2015; 33 (31): 3635–3640. doi: 10.1200/JCO.2014.59.9258.

57. Musilova K, Mraz M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia 2015; 29 (5): 1004–1017. doi: 10.1038/leu.2014.351.

58. Calin GA, Dumitru CD, Shimizu M et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002; 99 (24): 15524–15529.

59. Ventura A, Young AG, Winslow MM et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 2008; 132 (5): 875–886. doi: 10.1016/j.cell.2008.02.019.

60. Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 2010; 467 (7311): 86–90. doi: 10.1038/nature09284.

61. Thompson RC, Vardinogiannis I, Gilmore TD. Identification of an NF-κB p50/p65-responsive site in the human MIR155HG promoter. BMC Mol Biol 2013; 14: 24. doi: 10.1186/1471-2199-14-24.

62. Rai D, Kim SW, McKeller MR et al. Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci U S A 2010; 107 (7): 3111–3116. doi: 10.1073/pnas.0910667107.

63. Costinean S, Zanesi N, Pekarsky Y et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E (mu) -miR155 transgenic mice. Proc Natl Acad Sci U S A 2006; 103 (18): 7024–7029.

64. Cheng CJ, Bahal R, Babar IA et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 2015; 518 (7537): 107–110. doi: 10.1038/nature13905.

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