Interferon regulatory factor 4 involvement in the pathogenesis and development of B cell or plasma cell tumors: an update of research progresses_West China Medical Journal

Authors：

CHEN Jing , TANG Wenjiao ,  ZHANG Li , PAN Ling

Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Li, Email: drzhangli2014@sina.com

Keywords：

Interferon regulatory factor4; B cell; plasma cell; lymphoma; leukemia; myeloma

DOI：

10.7507/1002-0179.202305108

Video：

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Interferon regulatory factor 4 (IRF4) is one of the transcription factors in the interferon regulatory factor family. In the normal physiological process, IRF4 protein is a key factor regulating B cell development, such as early B cell development, pre-B cell switch recombination, mature B cell somatic hypermutation, and also a key factor regulating plasma cell differentiation. In addition, in recent years, it has been reported that Irf4 gene abnormalities or abnormal protein expression is closely involved in the occurrence and development of a variety of B cell or plasma cell tumors. This article reviews the physiological role of IRF4 in the differentiation and maturation of B cell or plasma cells, how IRF4 participates in the occurrence and development of B cell or plasma cell tumors, and its potential therapeutic target for B cell or plasma cell tumors.

1.	Sundararaj S, Casarotto MG. Molecular interactions of IRF4 in B cell development and malignancies. Biophys Rev, 2021, 13(6): 1219-1227.
2.	Amanda S, Tan TK, Iida S, et al. Lineage- and stage-specific oncogenicity of IRF. Exp Hematol, 2022, 114: 9-17.
3.	丁宇斌, 唐旭东. 骨髓增生异常综合征进展过程中核心基因的生物信息学分析. 临床与实验病理学杂志, 2022, 38(3): 344-347.
4.	Betzler AC, Ushmorov A, Brunner C. The transcriptional program during germinal center reaction - a close view at GC B cells, Tfh cells and Tfr cells. Front Immunol, 2023, 14: 1125503.
5.	Ottens K, Satterthwaite AB. IRF4 has a unique role in early B cell development and acts prior to CD21 expression to control marginal Zone B Cell Numbers. Front Immunol, 2021, 12: 779085.
6.	Maffei R, Fiorcari S, Atene CG, et al. The dynamic functions of IRF4 in B cell malignancies. Clin Exp Med, 2022, 23(4): 1171-1180.
7.	Wang G, Zou D, Wang Y, et al. IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection. J Heart Lung Transplant, 2021, 40(10): 1122-1132.
8.	Wong RWJ, Ong JZL, Theardy MS, et al. IRF4 as an oncogenic master transcription factor. Cancers (Basel), 2022, 14(17): 4314.
9.	Ochiai K, Yamaoka M, Swaminathan A, et al. Chromatin protein PC4 orchestrates B cell differentiation by collaborating with IKAROS and IRF4. Cell Rep, 2020, 33(12): 108517.
10.	Grundström C, Grundström T. The transcription factor E2A can bind to and cleave single-stranded immunoglobulin heavy chain locus DNA. Mol Immunol, 2023, 153: 51-59.
11.	Cook SL, Sievert EP, Sciammas R. B cell intrinsic IRF4 haploinsufficiency impairs affinity maturation. J Immunol, 2021, 207(12): 2992-3003.
12.	McGettigan SE, Debes GF. Immunoregulation by antibody secreting cells in inflammation, infection, and cancer. Immunol Rev, 2021, 303(1): 103-118.
13.	Merino Tejero E, Lashgari D, García-Valiente R, et al. Multiscale modeling of germinal center recapitulates the temporal transition from memory B cells to plasma cells differentiation as regulated by antigen affinity-based Tfh cell help. Front Immunol, 2021, 11: 620716.
14.	Benatti S, Atene CG, Fiorcari S, et al. IRF4 L116R mutation promotes proliferation of chronic lymphocytic leukemia B cells inducing MYC. Hematol Oncol, 2021, 39(5): 707-711.
15.	Maffei R, Fiorcari S, Benatti S, et al. IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK. Leukemia, 2021, 35(5): 1330-1343.
16.	Harris RA, Gary EB, Rout ED, et al. Detection and characterization of paraproteinemia in canine chronic B-cell lymphocytic leukemia using routine and free light chain immunofixation. Vet Clin Pathol, 2022, 51(4): 551-559.
17.	Asslaber D, Qi Y, Maeding N, et al. B-cell specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion. Blood, 2019, 134(20): 1717-1729.
18.	Kikushige Y. Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies. J Clin Exp Hematop, 2020, 60(4): 146-158.
19.	Wang J, Clay-Gilmour AI, Karaesmen E, et al. Genome-wide association analyses identify variants in IRF4 associated with acute myeloid leukemia and myelodysplastic syndrome susceptibility. Front Genet, 2021, 12: 554948.
20.	Frauenfeld L, Castrejon-de-Anta N, Ramis-Zaldivar JE, et al. Diffuse large B-cell lymphomas in adults with aberrant coexpression of CD10, BCL6, and MUM1 are enriched in IRF4 rearrangements. Blood Adv, 2022, 6(7): 2361-2372.
21.	Wong RWJ, Tan TK, Amanda S, et al. Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma. Blood, 2020, 135(12): 934-947.
22.	Wang L, Yuan W, Li L, et al. Immunogenomic-based analysis of hierarchical clustering of diffuse large cell lymphoma. J Immunol Res, 2022, 2022: 9544827.
23.	Hartert KT, Wenzl K, Krull JE, et al. Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL. Leukemia, 2021, 35(2): 522-533.
24.	Ramis-Zaldivar JE, Gonzalez-Farré B, Balagué O, et al. Distinct molecular profile of IRF4-rearranged large B-cell lymphoma. Blood, 2020, 135(4): 274-286.
25.	Jiang XN, Yu F, Xue T, et al. IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B‐cell lymphoma. Cancer Med, 2023, 12(9): 10684-10693.
26.	Nagel S, Meyer C, Eberth S, et al. Downregulation of STAT3 in epstein-barr virus-positive hodgkin lymphoma. Biomedicines, 2022, 10(7): 1608.
27.	Maco M, Kupcova K, Herman V, et al. Circulating tumor DNA in hodgkin lymphoma. Ann Hematol, 2022, 101(11): 2393-2403.
28.	Satou A, Asano N, Kato S, et al. Prognostic impact of MUM1/IRF4 expression in burkitt lymphoma (BL): a reappraisal of 88 BL patients in Japan. Am J Surg Pathol, 2017, 41(3): 389-395.
29.	Bristol JA, Brand J, Ohashi M, et al. Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells. PLoS Pathog, 2022, 18(4): e1010453.
30.	Rosemarie Q, Sugden B. Epstein-barr virus: how its lytic phase contributes to oncogenesis. Microorganisms, 2020, 8(11): 1824.
31.	Sacco A, Federico C, Giacomini A, et al. Halting the FGF/FGFR axis leads to antitumor activity in Waldenström’s macroglobulinemia by silencing MYD88. Blood, 2021, 137(18): 2495-2508.
32.	Zuo X, Liu D. Mechanism of immunomodulatory drug resistance and novel therapeutic strategies in multiple myeloma. Hematology, 2022, 27(1): 1110-1121.
33.	Fedele PL, Liao Y, Gong JN, et al. The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival. Leukemia, 2021, 35(7): 2114-2118.
34.	Tang TF, Chan YT, Cheong HC, et al. Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis. Cell Immunol, 2022, 380: 104594.
35.	Schleussner N, Cauchy P, Franke V, et al. Transcriptional reprogramming by mutated IRF4 in lymphoma. Nat Commun, 2023, 14(1): 6947.
36.	Pasqualucci L, Klein U. NF-κB mutations in germinal center B-cell lymphomas: relation to NF-κB function in normal B cells. Biomedicines, 2022, 10(10): 2450.
37.	Wu Y, Gu H, Bao Y, et al. USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma. Cell Biochem Funct, 2022, 40(4): 379-390.
38.	Mondala PK, Vora AA, Zhou T, et al. Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Cell Stem Cell, 2021, 28(4): 623-636. e9.

1. Sundararaj S, Casarotto MG. Molecular interactions of IRF4 in B cell development and malignancies. Biophys Rev, 2021, 13(6): 1219-1227.
2. Amanda S, Tan TK, Iida S, et al. Lineage- and stage-specific oncogenicity of IRF. Exp Hematol, 2022, 114: 9-17.
3. 丁宇斌, 唐旭东. 骨髓增生异常综合征进展过程中核心基因的生物信息学分析. 临床与实验病理学杂志, 2022, 38(3): 344-347.
4. Betzler AC, Ushmorov A, Brunner C. The transcriptional program during germinal center reaction - a close view at GC B cells, Tfh cells and Tfr cells. Front Immunol, 2023, 14: 1125503.
5. Ottens K, Satterthwaite AB. IRF4 has a unique role in early B cell development and acts prior to CD21 expression to control marginal Zone B Cell Numbers. Front Immunol, 2021, 12: 779085.
6. Maffei R, Fiorcari S, Atene CG, et al. The dynamic functions of IRF4 in B cell malignancies. Clin Exp Med, 2022, 23(4): 1171-1180.
7. Wang G, Zou D, Wang Y, et al. IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection. J Heart Lung Transplant, 2021, 40(10): 1122-1132.
8. Wong RWJ, Ong JZL, Theardy MS, et al. IRF4 as an oncogenic master transcription factor. Cancers (Basel), 2022, 14(17): 4314.
9. Ochiai K, Yamaoka M, Swaminathan A, et al. Chromatin protein PC4 orchestrates B cell differentiation by collaborating with IKAROS and IRF4. Cell Rep, 2020, 33(12): 108517.
10. Grundström C, Grundström T. The transcription factor E2A can bind to and cleave single-stranded immunoglobulin heavy chain locus DNA. Mol Immunol, 2023, 153: 51-59.
11. Cook SL, Sievert EP, Sciammas R. B cell intrinsic IRF4 haploinsufficiency impairs affinity maturation. J Immunol, 2021, 207(12): 2992-3003.
12. McGettigan SE, Debes GF. Immunoregulation by antibody secreting cells in inflammation, infection, and cancer. Immunol Rev, 2021, 303(1): 103-118.
13. Merino Tejero E, Lashgari D, García-Valiente R, et al. Multiscale modeling of germinal center recapitulates the temporal transition from memory B cells to plasma cells differentiation as regulated by antigen affinity-based Tfh cell help. Front Immunol, 2021, 11: 620716.
14. Benatti S, Atene CG, Fiorcari S, et al. IRF4 L116R mutation promotes proliferation of chronic lymphocytic leukemia B cells inducing MYC. Hematol Oncol, 2021, 39(5): 707-711.
15. Maffei R, Fiorcari S, Benatti S, et al. IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK. Leukemia, 2021, 35(5): 1330-1343.
16. Harris RA, Gary EB, Rout ED, et al. Detection and characterization of paraproteinemia in canine chronic B-cell lymphocytic leukemia using routine and free light chain immunofixation. Vet Clin Pathol, 2022, 51(4): 551-559.
17. Asslaber D, Qi Y, Maeding N, et al. B-cell specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion. Blood, 2019, 134(20): 1717-1729.
18. Kikushige Y. Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies. J Clin Exp Hematop, 2020, 60(4): 146-158.
19. Wang J, Clay-Gilmour AI, Karaesmen E, et al. Genome-wide association analyses identify variants in IRF4 associated with acute myeloid leukemia and myelodysplastic syndrome susceptibility. Front Genet, 2021, 12: 554948.
20. Frauenfeld L, Castrejon-de-Anta N, Ramis-Zaldivar JE, et al. Diffuse large B-cell lymphomas in adults with aberrant coexpression of CD10, BCL6, and MUM1 are enriched in IRF4 rearrangements. Blood Adv, 2022, 6(7): 2361-2372.
21. Wong RWJ, Tan TK, Amanda S, et al. Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma. Blood, 2020, 135(12): 934-947.
22. Wang L, Yuan W, Li L, et al. Immunogenomic-based analysis of hierarchical clustering of diffuse large cell lymphoma. J Immunol Res, 2022, 2022: 9544827.
23. Hartert KT, Wenzl K, Krull JE, et al. Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL. Leukemia, 2021, 35(2): 522-533.
24. Ramis-Zaldivar JE, Gonzalez-Farré B, Balagué O, et al. Distinct molecular profile of IRF4-rearranged large B-cell lymphoma. Blood, 2020, 135(4): 274-286.
25. Jiang XN, Yu F, Xue T, et al. IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B‐cell lymphoma. Cancer Med, 2023, 12(9): 10684-10693.
26. Nagel S, Meyer C, Eberth S, et al. Downregulation of STAT3 in epstein-barr virus-positive hodgkin lymphoma. Biomedicines, 2022, 10(7): 1608.
27. Maco M, Kupcova K, Herman V, et al. Circulating tumor DNA in hodgkin lymphoma. Ann Hematol, 2022, 101(11): 2393-2403.
28. Satou A, Asano N, Kato S, et al. Prognostic impact of MUM1/IRF4 expression in burkitt lymphoma (BL): a reappraisal of 88 BL patients in Japan. Am J Surg Pathol, 2017, 41(3): 389-395.
29. Bristol JA, Brand J, Ohashi M, et al. Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells. PLoS Pathog, 2022, 18(4): e1010453.
30. Rosemarie Q, Sugden B. Epstein-barr virus: how its lytic phase contributes to oncogenesis. Microorganisms, 2020, 8(11): 1824.
31. Sacco A, Federico C, Giacomini A, et al. Halting the FGF/FGFR axis leads to antitumor activity in Waldenström’s macroglobulinemia by silencing MYD88. Blood, 2021, 137(18): 2495-2508.
32. Zuo X, Liu D. Mechanism of immunomodulatory drug resistance and novel therapeutic strategies in multiple myeloma. Hematology, 2022, 27(1): 1110-1121.
33. Fedele PL, Liao Y, Gong JN, et al. The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival. Leukemia, 2021, 35(7): 2114-2118.
34. Tang TF, Chan YT, Cheong HC, et al. Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis. Cell Immunol, 2022, 380: 104594.
35. Schleussner N, Cauchy P, Franke V, et al. Transcriptional reprogramming by mutated IRF4 in lymphoma. Nat Commun, 2023, 14(1): 6947.
36. Pasqualucci L, Klein U. NF-κB mutations in germinal center B-cell lymphomas: relation to NF-κB function in normal B cells. Biomedicines, 2022, 10(10): 2450.
37. Wu Y, Gu H, Bao Y, et al. USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma. Cell Biochem Funct, 2022, 40(4): 379-390.
38. Mondala PK, Vora AA, Zhou T, et al. Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Cell Stem Cell, 2021, 28(4): 623-636. e9.

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