Transformace indolentního folikulární lymfomu v difuzní velkobuněčný B-lymfom – molekulární podstata „nádorové agresivity“

Czech version

Authors: F. Kledus ^1,2; D. Filip ^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 2023; 36(5): 353-363
Category: Review
doi: https://doi.org/10.48095/ccko2023353

Overview

Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin‘s lymphoma in the Western world. It is an indolent disease in most patients, but about 20% of patients experience an early relapse after initial treatment, which is associated with shorter overall survival. A histological transformation into an aggressive lymphoma, most frequently diffuse large-cell B-lymphoma, represents another prognostically unfavorable event in the course of the disease. Thanks to recent genomic studies and mouse models, we are able to better understand the molecular nature of the FL onset and evolution of “aggressive” subclones of cells. Recently, deregulation of several molecular pathways associated with the histological transformation has also been described.

Purpose: This review summarizes the complex molecular mechanisms responsible for FL onset, progression, aggressiveness, and transformation. We believe that the observations in FL have some general implications for understanding the mechanisms leading to the evolution of cancer “aggressiveness,” such as divergent evolution, intraclonal variability and tumor plasticity.

Keywords:

Diffuse large B-cell lymphoma – follicular lymphoma – transformed follicular lymphoma – histological transformation – molecular mechanisms

Sources

1. Salles G, Seymour JF, Offner F et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377 (9759): 42–51. doi: 10.1016/S0140-6736 (10) 62175-7.

2. Casulo C, Byrtek M, Dawson KL et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines 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.

3. Federico M, Caballero Barrigón MD, Marcheselli L et al. Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis. Lancet Haematol 2018; 5 (8): e359–e367. doi: 10.1016/S2352-3026 (18) 30090-5.

4. Devan J, Janikova A, Mraz M. New concepts in follicular lymphoma biology: from BCL2 to epigenetic regulators and non-coding RNAs. Semin Oncol 2018; 45 (5–6): 291–302. doi: 10.1053/j.seminoncol.2018.07. 005.

5. Roulland S, Faroudi M, Mamessier E et al. Early steps of follicular lymphoma pathogenesis. Adv Immunol 2011; 111: 1–46. doi: 10.1016/B978-0-12-385991-4.00001-5.

6. Sungalee S, Mamessier E, Morgado E et al. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression. J Clin Invest 2014; 124 (12): 5337–5351. doi: 10.1172/JCI72415.

7. 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.

8. Kridel R, Chan FC, Mottok A et al. Histological transformation and progression in follicular lymphoma: a clonal evolution study. PLoS Med 2016; 13 (12): e1002197. doi: 10.1371/journal.pmed.1002197.

9. 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.

10. Bouska A, Zhang W, Gong Q et al. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 2017; 31 (1): 83–91. doi: 10.1038/leu.2016.175.

11. 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.

12. Green MR, Gentles AJ, Nair RV et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 2013; 121 (9): 1604–1611. doi: 10.1182/blood-2012-09-457283.

13. Radcliffe CM, Arnold JN, Suter DM et al. Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J Biol Chem 2007; 282 (10): 7405–7415. doi: 10.1074/jbc.M602690200.

14. Linley A, Krysov S, Ponzoni M et al. Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells. Blood 2015; 126 (16): 1902–1910. doi: 10.1182/blood-2015-04-640805.

15. Amin R, Mourcin F, Uhel F et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood 2015; 126 (16): 1911–1920. doi: 10.1182/blood-2015-04-640912.

16. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013; 12 (3): 229–243. doi: 10.1038/nrd3937.

17. Huet S, Sujobert P, Salles G. From genetics to the clinic: a translational perspective on follicular lymphoma. Nat Rev Cancer 2018; 18 (4): 224–239. doi: 10.1038/nrc.2017.127.

18. Mourcin F, Verdière L, Roulois D et al. Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape. Immunity 2021; 54 (8): 1788–1806.e7. doi: 10.1016/j.immuni.2021.05.019.

19. Han G, Deng Q, Marques-Piubelli ML et al. Follicular lymphoma microenvironment characteristics associated with tumor cell mutations and MHC class II expression. Blood Cancer Discov 2022; 3 (5): 428–443. doi: 10.1158/2643-3230.BCD-21-0075.

20. Béguelin W, Teater M, Meydan C et al. Mutant EZH2 induces a pre-malignant lymphoma Niche by reprogramming the immune response. Cancer Cell 2020; 37 (5): 655–673.e11. doi: 10.1016/j.ccell.2020.04.004.

21. Araf S, Wang J, Korfi K et al. Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma. Leukemia 2018; 32 (5): 1261–1265. doi: 10.1038/s41375-018-0043-y.

22. Haebe S, Shree T, Sathe A et al. Single-cell analysis can define distinct evolution of tumor sites in follicular lymphoma. Blood 2021; 137 (21): 2869–2880. doi: 10.1182/blood.2020009855.

23. Glas AM, Knoops L, Delahaye L et al. Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. J Clin Oncol 2007; 25 (4): 390–398. doi: 10.1200/JCO.2006.06.1648.

24. Crouch S, Painter D, Barrans SL et al. Molecular subclusters of follicular lymphoma: a report from the United Kingdom’s Haematological Malignancy Research Network. Blood Adv 2022; 6 (21): 5716–5731. doi: 10.1182/bloodadvances.2021005284.

25. Musilova K, Devan J, Cerna K et al. miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels. Blood 2018; 132 (22): 2389–2400. doi: 10.1182/blood-2018-06-855502.

26. 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.

27. 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.

28. Victora GD, Dominguez-Sola D, Holmes AB et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 2012; 120 (11): 2240–2248. doi: 10.1182/blood-2012-03-415380.

29. Filip D, Mraz M. The role of MYC in the transformation and aggressiveness of „indolent“ B-cell malignancies. Leuk Lymphoma 2020; 61 (3): 510–524. doi: 10.1080/10428194.2019.1675877.

30. Alaggio R, Amador C, Anagnostopoulos I et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia 2022; 36 (7): 1720–1748. doi: 10.1038/s41375-022-01620-2.

31. Cucco F, Barrans S, Sha C et al. Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit. Leukemia 2020; 34 (5): 1329–1341. doi: 10.1038/s41375-019-0691-6.

32. Hoferkova E, Kadakova S, Mraz M. In vitro and in vivo models of CLL-T cell interactions: implications for drug testing. Cancers 2022; 14 (13): 3087. doi: 10.3390/cancers14133087.

33. Sharma S, Pavlasova GM, Seda V et al. miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors. Blood 2021; 137 (18): 2481–2494. doi: 10.1182/blood.2020005 627.

34. Mottok A, Jurinovic V, Farinha P et al. FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy. Blood 2018; 131 (2): 226–235. doi: 10.1182/blood-2017-08-799 080.

35. Cerna K, Oppelt J, Chochola V et al. MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells. Leukemia 2019; 33 (2): 403–414. doi: 10.1038/s41375-018-0230-x.

36. Lou X, Fu J, Zhao X et al. MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages. J Exp Clin Cancer Res 2020; 39 (1): 237. doi: 10.1186/s13046-020-01747-z.

37. Mihailovich M, Bremang M, Spadotto V et al. miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth. Nat Commun 2015; 6 (1): 8725. doi: 10.1038/ncomms9725.

38. Seda V, Vojackova E, Ondrisova L et al. FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia. Blood 2021; 138 (9): 758–772. doi: 10.1182/blood.2020008101.

39. Dominguez-Sola D, Kung J, Holmes AB et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 2015; 43 (6): 1064–1074. doi: 10.1016/j.immuni.2015.10.015.

40. Kridel R, Mottok A, Farinha P et al. Cell of origin of transformed follicular lymphoma. Blood 2015; 126 (18): 2118–2127. doi: 10.1182/blood-2015-06-649905.

41. van Eijk M, Defrance T, Hennino A et al. Death-receptor contribution to the germinal-center reaction. Trends Immunol 2001; 22 (12): 677–682. doi: 10.1016/s1471-4906 (01) 02086-5.

42. Cheung KJJ, Johnson NA, Affleck JG et al. Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res 2010; 70 (22): 9166–9174. doi: 10.1158/0008-5472.CAN-10-2460.

43. Mintz MA, Felce JH, Chou MY et al. The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis. Immunity 2019; 51 (2): 310–323.e7. doi: 10.1016/j.immuni.2019.05.022.

44. Challa-Malladi M, Lieu YK, Califano O et al. Combined genetic inactivation of b2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011; 20 (6): 728–740. doi: 10.1016/j.ccr.2011.11.006.

45. Muppidi JR, Schmitz R, Green JA et al. Loss of signalling via Ga13 in germinal centre B-cell-derived lymphoma. Nature 2014; 516 (7530): 254–258. doi: 10.1038/nature13765.

46. Morin RD, Mungall K, Pleasance E et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 2013; 122 (7): 1256–1265. doi: 10.1182/blood-2013-02-483727.

47. Pfeifer M, Grau M, Lenze D et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci 2013; 110 (30): 12420–12425. doi: 10.1073/pnas.13056 56110.

48. Lossos IS, Alizadeh AA, Diehn M et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci 2002; 99 (13): 8886–8891. doi: 10.1073/pnas.132253599.

49. Lawrie CH, Chi J, Taylor S et al. Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma. J Cell Mol Med 2009; 13 (7): 1248–1260. doi: 10.1111/j.1582-4934.2008.00628.x.

50. Sarkozy C, Maurer MJ, Link BK et al. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of French and US cohorts. J Clin Oncol 2019; 37 (2): 144–152. doi: 10.1200/JCO.18.00 400.

51. Llombart V, Mansour MR. Therapeutic targeting of „undruggable” MYC. EBioMedicine 2022; 75: 103756. doi: 10.1016/j.ebiom.2021.103756.

52. Kridel R, Sehn LH, Gascoyne RD. Can histologic transformation of follicular lymphoma be predicted and prevented? Blood 2017; 130 (3): 258–266. doi: 10.1182/blood-2017-03-691345.

53. Schmitz R, Wright GW, Huang DW et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med 2018; 378 (15): 1396–1407. doi: 10.1056/NEJM- oa1801445.