4 Summary and outlook
CRISPR/Cas9 technology, as a novel technology, has the potential to permanently destroy tumor genes, which is not only simpler and faster in design and synthesis, but also creates new avenues for the study of tumor pathogenesis, screening of drug-acting gene targets and precision medicine, and has become a hot spot for many researches in recent years.
At present, B cell lymphoma is mostly treated by chemotherapy. However, patients are susceptible to drug resistance, so it is important to develop a new treatment for the disease. Based on this, the researchers developed a new treatment, targeting gene therapy, which gives hope to B-cell lymphoma patients and is expected to solve the treatment challenges of the disease. But more research is needed to learn more about CRISPR gene editing and its role in disease and to combine it with other treatments to cure B-cell lymphoma. While some problems remain unresolved, I believe that with continuous improvement, this technology can be applied to areas such as medicine in the future.
References
1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood . May 19 2016;127(20):2391-405. doi:10.1182/blood-2016-03-643544
2. Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science . Sep 5 2014;345(6201):1184-1188. doi:10.1126/science.1254445
3. Frangoul H, Ho TW, Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. Reply. N Engl J Med . Jun 10 2021;384(23):e91. doi:10.1056/NEJMc2103481
4. Miller JC, Holmes MC, Wang J, et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol . Jul 2007;25(7):778-85. doi:10.1038/nbt1319
5. Wood AJ, Lo TW, Zeitler B, et al. Targeted genome editing across species using ZFNs and TALENs. Science . Jul 15 2011;333(6040):307. doi:10.1126/science.1207773
6. Zhang F, Cong L, Lodato S, Kosuri S, Church GM, Arlotta P. Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nat Biotechnol . Feb 2011;29(2):149-53. doi:10.1038/nbt.1775
7. Workman RE, Pammi T, Nguyen BTK, et al. A natural single-guide RNA repurposes Cas9 to autoregulate CRISPR-Cas expression. Cell . Feb 4 2021;184(3):675-688 e19. doi:10.1016/j.cell.2020.12.017
8. Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol . Aug 2019;20(8):490-507. doi:10.1038/s41580-019-0131-5
9. Marraffini LA. CRISPR-Cas immunity in prokaryotes. Nature . Oct 1 2015;526(7571):55-61. doi:10.1038/nature15386
10. Mojica FJ, Rodriguez-Valera F. The discovery of CRISPR in archaea and bacteria. FEBS J . Sep 2016;283(17):3162-9. doi:10.1111/febs.13766
11. Shmakov S, Abudayyeh OO, Makarova KS, et al. Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems.Mol Cell . Nov 5 2015;60(3):385-97. doi:10.1016/j.molcel.2015.10.008
12. Shmakov S, Smargon A, Scott D, et al. Diversity and evolution of class 2 CRISPR-Cas systems. Nature Reviews Microbiology . Mar 2017;15(3):169-182. doi:10.1038/nrmicro.2016.184
13. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science . Aug 17 2012;337(6096):816-21. doi:10.1126/science.1225829
14. Deltcheva E, Chylinski K, Sharma CM, et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature . Mar 31 2011;471(7340):602-7. doi:10.1038/nature09886
15. Liao C, Sharma S, Svensson SL, et al. Spacer prioritization in CRISPR-Cas9 immunity is enabled by the leader RNA. Nat Microbiol . Apr 2022;7(4):530-541. doi:10.1038/s41564-022-01074-3
16. Gasiunas G, Barrangou R, Horvath P, Siksnys V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci U S A . Sep 25 2012;109(39):E2579-86. doi:10.1073/pnas.1208507109
17. Joung J, Engreitz JM, Konermann S, et al. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood.Nature . Aug 17 2017;548(7667):343-346. doi:10.1038/nature23451
18. Shalem O, Sanjana NE, Hartenian E, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science . Jan 3 2014;343(6166):84-87. doi:10.1126/science.1247005
19. Zhu S, Li W, Liu J, et al. Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library.Nat Biotechnol . Dec 2016;34(12):1279-1286. doi:10.1038/nbt.3715
20. Korkmaz G, Lopes R, Ugalde AP, et al. Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9. Nat Biotechnol . Feb 2016;34(2):192-8. doi:10.1038/nbt.3450
21. Braendstrup P, Levine BL, Ruella M. The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19. Cytotherapy . Feb 2020;22(2):57-69. doi:10.1016/j.jcyt.2019.12.004
22. Roex G, Feys T, Beguin Y, et al. Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Pharmaceutics . Feb 24 2020;12(2)doi:10.3390/pharmaceutics12020194
23. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A . Dec 1989;86(24):10024-8. doi:10.1073/pnas.86.24.10024
24. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med . Oct 16 2014;371(16):1507-17. doi:10.1056/NEJMoa1407222
25. Frey NV, Gill S, Hexner EO, et al. Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol . Sep 1 2020;38(25):2862-2871. doi:10.1200/JCO.19.03237
26. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition.Clin Cancer Res . May 1 2017;23(9):2255-2266. doi:10.1158/1078-0432.CCR-16-1300
27. Ren J, Zhang X, Liu X, et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget . Mar 7 2017;8(10):17002-17011. doi:10.18632/oncotarget.15218
28. Upadhyay R, Boiarsky JA, Pantsulaia G, et al. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.Cancer Discov . Mar 2021;11(3):599-613. doi:10.1158/2159-8290.CD-20-0756
29. Barré FPY, Claes BSR, Dewez F, et al. Specific Lipid and Metabolic Profiles of R-CHOP-Resistant Diffuse Large B-Cell Lymphoma Elucidated by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging and in Vivo Imaging. Anal Chem . Dec 18 2018;90(24):14198-14206. doi:10.1021/acs.analchem.8b02910
30. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.Blood . Oct 19 2017;130(16):1800-1808. doi:10.1182/blood-2017-03-769620
31. Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol . Mar 2015;15(3):172-84. doi:10.1038/nri3814
32. Caeser R, Di Re M, Krupka JA, et al. Genetic modification of primary human B cells to model high-grade lymphoma. Nat Commun . Oct 4 2019;10(1):4543. doi:10.1038/s41467-019-12494-x
33. Pasqualucci L, Khiabanian H, Fangazio M, et al. Genetics of follicular lymphoma transformation. Cell Rep . Jan 16 2014;6(1):130-40. doi:10.1016/j.celrep.2013.12.027
34. Green MR, Gentles AJ, Nair RV, et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma.Blood . Feb 28 2013;121(9):1604-11. doi:10.1182/blood-2012-09-457283
35. Hashwah H, Schmid CA, Kasser S, et al. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. Proc Natl Acad Sci U S A . Sep 5 2017;114(36):9701-9706. doi:10.1073/pnas.1619555114
36. Jiang Y, Ortega-Molina A, Geng H, et al. CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Cancer Discov . Jan 2017;7(1):38-53. doi:10.1158/2159-8290.CD-16-0975
37. Zhang J, Vlasevska S, Wells VA, et al. The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma. Cancer Discov . Mar 2017;7(3):322-337. doi:10.1158/2159-8290.Cd-16-1417
38. Chu CS, Hellmuth JC, Singh R, et al. Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage. Mol Cell . Dec 3 2020;80(5):845-861 e10. doi:10.1016/j.molcel.2020.10.036
39. Bunting KL, Soong TD, Singh R, et al. Multi-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region. Immunity . Sep 20 2016;45(3):497-512. doi:10.1016/j.immuni.2016.08.012
40. Calado DP, Sasaki Y, Godinho SA, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol . Nov 2012;13(11):1092-100. doi:10.1038/ni.2418
41. Dominguez-Sola D, Victora GD, Ying CY, et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry.Nat Immunol . Nov 2012;13(11):1083-91. doi:10.1038/ni.2428
42. Dietz A, Dalda N, Zielke S, et al. Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B-cell lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis. Int J Cancer . Sep 1 2020;147(5):1485-1498. doi:10.1002/ijc.32976
43. Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol . Jun 2015;16(6):329-44. doi:10.1038/nrm3999
44. Yang Y, Kelly P, Shaffer AL, 3rd, et al. Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma. Cancer Cell . Apr 11 2016;29(4):494-507. doi:10.1016/j.ccell.2016.03.006
45. Mo Z, Wood S, Namiranian S, et al. Deciphering the mechanisms of CC-122 resistance in DLBCL via a genome-wide CRISPR screen. Blood Adv . Apr 13 2021;5(7):2027-2039. doi:10.1182/bloodadvances.2020003431
46. Hagner PR, Man HW, Fontanillo C, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood . Aug 6 2015;126(6):779-89. doi:10.1182/blood-2015-02-628669
47. Zhou X, Chen N, Xu H, et al. Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma. J Hematol Oncol . Jun 16 2020;13(1):77. doi:10.1186/s13045-020-00906-1
48. Stelling A, Hashwah H, Bertram K, Manz MG, Tzankov A, Müller A. The tumor suppressive TGF-β/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. Blood . May 17 2018;131(20):2235-2246. doi:10.1182/blood-2017-10-810630
49. Bhalla K, Jaber S, Reagan K, et al. SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma. Sci Rep . Dec 3 2020;10(1):21159. doi:10.1038/s41598-020-78193-6
50. Morita A, Tanimoto K, Murakami T, Morinaga T, Hosoi Y. Mitochondria are required for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line Hep G2 cells. Biochem Biophys Res Commun . Jan 24 2014;443(4):1286-90. doi:10.1016/j.bbrc.2013.12.139
51. Guo R, Jiang C, Zhang Y, et al. MYC Controls the Epstein-Barr Virus Lytic Switch. Mol Cell . May 21 2020;78(4):653-669 e8. doi:10.1016/j.molcel.2020.03.025
52. Guo R, Zhang Y, Teng M, et al. Author Correction: DNA methylation enzymes and PRC1 restrict B-cell Epstein-Barr virus oncoprotein expression. Nat Microbiol . Jun 2022;7(6):928. doi:10.1038/s41564-022-01137-5
53. Sidorov S, Fux L, Steiner K, et al. CD4 + T cells are found within endemic Burkitt lymphoma and modulate Burkitt lymphoma precursor cell viability and expression of pathogenically relevant Epstein-Barr virus genes. Cancer Immunol Immunother . Jun 2022;71(6):1371-1392. doi:10.1007/s00262-021-03057-5
54. Koch A, Jeiler B, Roedig J, van Wijk SJL, Dolgikh N, Fulda S. Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt’s lymphoma cell lines. Neoplasia . May 2021;23(5):539-550. doi:10.1016/j.neo.2021.03.003
55. Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature . Jan 15 2015;517(7534):311-20. doi:10.1038/nature14191
56. Allen F, Crepaldi L, Alsinet C, et al. Predicting the mutations generated by repair of Cas9-induced double-strand breaks. Nat Biotechnol . Nov 27 2018;doi:10.1038/nbt.4317
57. Tafuku S, Matsuda T, Kawakami H, Tomita M, Yagita H, Mori N. Potential mechanism of resistance to TRAIL-induced apoptosis in Burkitt’s lymphoma. Eur J Haematol . Jan 2006;76(1):64-74. doi:10.1111/j.0902-4441.0000.t01-1-EJH2345.x
58. Zhang Y, Jiang C, Trudeau SJ, et al. Histone Loaders CAF1 and HIRA Restrict Epstein-Barr Virus B-Cell Lytic Reactivation. mBio . Oct 27 2020;11(5)doi:10.1128/mBio.01063-20
59. Faumont N, Durand-Panteix S, Schlee M, et al. c-Myc and Rel/NF-kappaB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells.J Virol . May 2009;83(10):5014-27. doi:10.1128/JVI.02264-08
60. Nagashima T, Ichimiya S, Kikuchi T, et al. Arachidonate 5-lipoxygenase establishes adaptive humoral immunity by controlling primary B cells and their cognate T-cell help. Am J Pathol . Jan 2011;178(1):222-32. doi:10.1016/j.ajpath.2010.11.033
61. Xia C, Sadeghi L, Straat K, et al. Intrinsic 5-lipoxygenase activity regulates migration and adherence of mantle cell lymphoma cells.Prostaglandins Other Lipid Mediat . Oct 2021;156:106575. doi:10.1016/j.prostaglandins.2021.106575
62. Jakobsson PJ, Shaskin P, Larsson P, et al. Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes. Eur J Biochem . Aug 15 1995;232(1):37-46. doi:10.1111/j.1432-1033.1995.tb20778.x
63. Luanpitpong S, Poohadsuan J, Samart P, Kiratipaiboon C, Rojanasakul Y, Issaragrisil S. Reactive oxygen species mediate cancer stem-like cells and determine bortezomib sensitivity via Mcl-1 and Zeb-1 in mantle cell lymphoma. Biochim Biophys Acta Mol Basis Dis . Nov 2018;1864(11):3739-3753. doi:10.1016/j.bbadis.2018.09.010
64. Thieme E, Liu T, Bruss N, et al. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma. Cell Death Dis . Mar 16 2022;13(3):246. doi:10.1038/s41419-022-04684-1
65. Miloudi H, Bohers E, Guillonneau F, et al. XPO1(E571K) Mutation Modifies Exportin 1 Localisation and Interactome in B-cell Lymphoma.Cancers (Basel) . Sep 30 2020;12(10)doi:10.3390/cancers12102829
66. Taylor J, Sendino M, Gorelick AN, et al. Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis. Cancer Discov . Oct 2019;9(10):1452-1467. doi:10.1158/2159-8290.Cd-19-0298
67. Barbarino V, Henschke S, Blakemore SJ, et al. Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2. Cancers (Basel) . Aug 15 2020;12(8)doi:10.3390/cancers12082303
68. Jiang C, Trudeau SJ, Cheong TC, et al. CRISPR/Cas9 Screens Reveal Multiple Layers of B cell CD40 Regulation. Cell Rep . Jul 30 2019;28(5):1307-1322 e8. doi:10.1016/j.celrep.2019.06.079
69. Gayle S, Landrette S, Beeharry N, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood . Mar 30 2017;129(13):1768-1778. doi:10.1182/blood-2016-09-736892