The role of genome composition and activation in shaping the translocation landscape in health and disease
Main Article Content
Abstract
Translocations are rearrangements produced upon erroneous repair of double-strand breaks, fusing segments of non-homologous chromosomes. These events can cause chimeric protein expression and other transcriptional alterations, eventually driving oncogenic transformation. Despite their significance, the factors shaping the heterogeneous translocation landscape in healthy individuals and cancer patients remain incompletely understood. In this review, we focus on genomic content and activation as two fundamental factors associated with translocation formation and selection. While emphasizing the critical role of double-strand breaks and interchromosomal contacts in translocation formation, we discuss that selective advantage is likely the main driver shaping translocation landscapes in health and disease. Finally, we address that it remains difficult to disentangle the effect of translocation formation from the influence of selective pressure, and point out that unraveling their separate contribution in future studies will be key to better understand early tumorigenesis.
Keywords:
Translocations, Genome Composition, Epigenetic Landscapes, Hematological Malignancies
Article Details
How to Cite
ONCINS, Anna; VELTEN, Jessica; BEEKMAN, Renée.
The role of genome composition and activation in shaping the translocation landscape in health and disease.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6212>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6212.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Nambiar M, Raghavan SC. Chromosomal translocations among the healthy human population: implications in oncogenesis. Cell Mol Life Sci. 2013;70(8):1381-1392.
2. Brassesco MS, Montaldi AP, Gras DE, et al. MLL leukemia-associated rearrangements in peripheral blood lymphocytes from healthy individuals. Genet Mol Biol. 2009;32(2):234-241.
3. Machado HE, Mitchell E, Øbro NF, et al. Diverse mutational landscapes in human lymphocytes. Nature. 2022;608(7924):724-732.
4. Willis TG, Dyer MJ. The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies. Blood. 2000;96(3):808-822.
5. Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 2017;130(4):410-423.
6. Ostashevsky JY. Higher-order structure of interphase chromosomes and radiation-induced chromosomal exchange aberrations. Int J Radiat Biol. 2000;76(9):1179-1187.
7. Lima MF de, Lisboa M de O, Terceiro LEL, Rangel-Pozzo A, Mai S. Chromosome territories in hematological malignancies. Cells. 2022;11(8):1368.
8. Gué M, Sun JS, Boudier T. Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited. BMC Cancer. 2006;6(1):20.
9. Roix J, McQueen P, Munson P, Parada L, Misteli T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nat Genet. 2003;34:287-291.
10. Zorn C, Cremer C, Cremer T, Zimmer J. Unscheduled DNA synthesis after partial UV irradiation of the cell nucleus. Distribution in interphase and metaphase. Exp Cell Res. 1979;124(1):111-119.
11. Girelli G, Custodio J, Kallas T, et al. GPSeq reveals the radial organization of chromatin in the cell nucleus. Nat Biotechnol. 2020;38(10):1184-1193.
12. Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA. Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol. 1999;145(6):1119-1131.
13. Cremer M, von Hase J, Volm T, et al. Non-random radial higher-order chromatin arrangements in nuclei of diploid human cells. Chromosome Res. 2001;9(7):541-567.
14. Sun HB, Shen J, Yokota H. Size-dependent positioning of human chromosomes in interphase nuclei. Biophys J. 2000;79(1):184-190.
15. Hsu TC. A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics. 1975;79 Suppl:137-150.
16. Tanabe H, Habermann FA, Solovei I, Cremer M, Cremer T. Non-random radial arrangements of interphase chromosome territories: evolutionary considerations and functional implications. Mutat Res. 2002;504(1-2):37-45.
17. Gazave E, Gautier P, Gilchrist S, Bickmore WA. Does radial nuclear organisation influence DNA damage? Chromosome Res. 2005;13(4):377-388.
18. Hardison RC, Roskin KM, Yang S, et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 2003;13(1):13-26.
19. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302(5909):575-581.
20. Siu G, Clark SP, Yoshikai Y, et al. The human T cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene. Cell. 1984;37(2):393-401.
21. Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248(4962):1517-1523.
22. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553-563.
23. Chiarle R, Zhang Y, Frock RL, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147(1):107-119.
24. Klein IA, Resch W, Jankovic M, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011;147(1):95-106.
25. Nadeu F, Martin-Garcia D, Clot G, et al. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood. 2020;136(12):1419-1432.
26. Tsai AG, Lu H, Raghavan SC, Muschen M, Hsieh CL, Lieber MR. Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity. Cell. 2008;135(6):1130-1142.
27. Turlan C, Chandler M. Playing second fiddle: second-strand processing and liberation of transposable elements from donor DNA. Trends Microbiol. 2000;8(6):268-274.
28. Curcio MJ, Derbyshire KM. The outs and ins of transposition: from mu to kangaroo. Nat Rev Mol Cell Biol. 2003;4(11):865-877.
29. Zhou L, Mitra R, Atkinson PW, Hickman AB, Dyda F, Craig NL. Transposition of hAT elements links transposable elements and V(D)J recombination. Nature. 2004;432(7020):995-1001.
30. Balachandran P, Walawalkar IA, Flores JI, Dayton JN, Audano PA, Beck CR. Transposable element-mediated rearrangements are prevalent in human genomes. Nat Commun. 2022;13(1):7115.
31. van Bree EJ, Guimarães RLFP, Lundberg M, et al. A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci. Genome Res. 2022;32(4):656-670.
32. Chen JM, Chuzhanova N, Stenson PD, Férec C, Cooper DN. Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions. Hum Mutat. 2005;26(4):362-373.
33. Elliott B, Richardson C, Jasin M. Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Mol Cell. 2005;17(6):885-894.
34. Mao YS, Zhang B, Spector DL. Biogenesis and function of nuclear bodies. Trends Genet. 2011;27(8):295-306.
35. Brown DD, Gurdon JB. Absence of ribosomal RNA synthesis in the anucleolate mutant of Xenopus laevis. Proc Natl Acad Sci U S A. 1964;51(1):139-146.
36. Sakai K, Ohta T, Minoshima S, et al. Human ribosomal RNA gene cluster: identification of the proximal end containing a novel tandem repeat sequence. Genomics. 1995;26(3):521-526.
37. Baranello L, Kouzine F, Wojtowicz D, et al. DNA break mapping reveals topoisomerase II activity genome-wide. Int J Mol Sci. 2014;15(7):13111-13122.
38. Crosetto N, Mitra A, Silva MJ, et al. Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing. Nat Methods. 2013;10(4):361-365.
39. Hutchins AP, Pei D. Transposable elements at the center of the crossroads between embryogenesis, embryonic stem cells, reprogramming, and long non-coding RNAs. Sci Bull (Beijing). 2015;60(20):1722-1733.
40. Wu K, Fan D, Zhao H, et al. Dynamics of histone acetylation during human early embryogenesis. Cell Discov. 2023;9(1):29.
41. Tumbar T, Belmont AS. Interphase movements of a DNA chromosome region modulated by VP16 transcriptional activator. Nat Cell Biol. 2001;3(2):134-139.
42. Dietzel S, Schiebel K, Little G, et al. The 3D positioning of ANT2 and ANT3 genes within female X chromosome territories correlates with gene activity. Exp Cell Res. 1999;252(2):363-375.
43. Wang H, Xu X, Nguyen CM, et al. CRISPR-mediated programmable 3D genome positioning and nuclear organization. Cell. 2018;175(5):1405-1417.e14.
44. Zink D, Amaral MD, Englmann A, et al. Transcription-dependent spatial arrangements of CFTR and adjacent genes in human cell nuclei. J Cell Biol. 2004;166(6):815-825.
45. Iborra FJ, Pombo A, Jackson DA, Cook PR. Active RNA polymerases are localized within discrete transcription "factories’ in human nuclei. J Cell Sci. 1996;109 ( Pt 6)(6):1427-1436.
46. de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990;347(6293):558-561.
47. de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300(5894):765-767.
48. Ortiz de Mendíbil I, Vizmanos JL, Novo FJ. Signatures of selection in fusion transcripts resulting from chromosomal translocations in human cancer. PLoS One. 2009;4(3):e4805.
49. Frenkel-Morgenstern M, Valencia A. Novel domain combinations in proteins encoded by chimeric transcripts. Bioinformatics. 2012;28(12):i67-74.
50. Shugay M, Ortiz de Mendíbil I, Vizmanos JL, Novo FJ. Genomic hallmarks of genes involved in chromosomal translocations in hematological cancer. PLoS Comput Biol. 2012;8(12):e1002797.
51. Wilhelm A, Marschalek R. The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11). Oncogene. 2021;40(42):6093-6102.
52. Bueno C, Calero-Nieto FJ, Wang X, et al. Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions. Haematologica. 2019;104(6):1189-1201.
53. Küppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20(40):5580-5594.
54. Cauwelier B, Dastugue N, Cools J, et al. Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbeta locus rearrangements and putative new T-cell oncogenes. Leukemia. 2006;20(7):1238-1244
55. Matharu NK, Ahanger SH. Chromatin insulators and topological domains: Adding new dimensions to 3D genome architecture. Genes (Basel). 2015;6(3):790-811.
56. Gröschel S, Sanders MA, Hoogenboezem R, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014;157(2):369-381.
2. Brassesco MS, Montaldi AP, Gras DE, et al. MLL leukemia-associated rearrangements in peripheral blood lymphocytes from healthy individuals. Genet Mol Biol. 2009;32(2):234-241.
3. Machado HE, Mitchell E, Øbro NF, et al. Diverse mutational landscapes in human lymphocytes. Nature. 2022;608(7924):724-732.
4. Willis TG, Dyer MJ. The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies. Blood. 2000;96(3):808-822.
5. Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 2017;130(4):410-423.
6. Ostashevsky JY. Higher-order structure of interphase chromosomes and radiation-induced chromosomal exchange aberrations. Int J Radiat Biol. 2000;76(9):1179-1187.
7. Lima MF de, Lisboa M de O, Terceiro LEL, Rangel-Pozzo A, Mai S. Chromosome territories in hematological malignancies. Cells. 2022;11(8):1368.
8. Gué M, Sun JS, Boudier T. Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited. BMC Cancer. 2006;6(1):20.
9. Roix J, McQueen P, Munson P, Parada L, Misteli T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nat Genet. 2003;34:287-291.
10. Zorn C, Cremer C, Cremer T, Zimmer J. Unscheduled DNA synthesis after partial UV irradiation of the cell nucleus. Distribution in interphase and metaphase. Exp Cell Res. 1979;124(1):111-119.
11. Girelli G, Custodio J, Kallas T, et al. GPSeq reveals the radial organization of chromatin in the cell nucleus. Nat Biotechnol. 2020;38(10):1184-1193.
12. Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA. Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol. 1999;145(6):1119-1131.
13. Cremer M, von Hase J, Volm T, et al. Non-random radial higher-order chromatin arrangements in nuclei of diploid human cells. Chromosome Res. 2001;9(7):541-567.
14. Sun HB, Shen J, Yokota H. Size-dependent positioning of human chromosomes in interphase nuclei. Biophys J. 2000;79(1):184-190.
15. Hsu TC. A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics. 1975;79 Suppl:137-150.
16. Tanabe H, Habermann FA, Solovei I, Cremer M, Cremer T. Non-random radial arrangements of interphase chromosome territories: evolutionary considerations and functional implications. Mutat Res. 2002;504(1-2):37-45.
17. Gazave E, Gautier P, Gilchrist S, Bickmore WA. Does radial nuclear organisation influence DNA damage? Chromosome Res. 2005;13(4):377-388.
18. Hardison RC, Roskin KM, Yang S, et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 2003;13(1):13-26.
19. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302(5909):575-581.
20. Siu G, Clark SP, Yoshikai Y, et al. The human T cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene. Cell. 1984;37(2):393-401.
21. Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248(4962):1517-1523.
22. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553-563.
23. Chiarle R, Zhang Y, Frock RL, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147(1):107-119.
24. Klein IA, Resch W, Jankovic M, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011;147(1):95-106.
25. Nadeu F, Martin-Garcia D, Clot G, et al. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood. 2020;136(12):1419-1432.
26. Tsai AG, Lu H, Raghavan SC, Muschen M, Hsieh CL, Lieber MR. Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity. Cell. 2008;135(6):1130-1142.
27. Turlan C, Chandler M. Playing second fiddle: second-strand processing and liberation of transposable elements from donor DNA. Trends Microbiol. 2000;8(6):268-274.
28. Curcio MJ, Derbyshire KM. The outs and ins of transposition: from mu to kangaroo. Nat Rev Mol Cell Biol. 2003;4(11):865-877.
29. Zhou L, Mitra R, Atkinson PW, Hickman AB, Dyda F, Craig NL. Transposition of hAT elements links transposable elements and V(D)J recombination. Nature. 2004;432(7020):995-1001.
30. Balachandran P, Walawalkar IA, Flores JI, Dayton JN, Audano PA, Beck CR. Transposable element-mediated rearrangements are prevalent in human genomes. Nat Commun. 2022;13(1):7115.
31. van Bree EJ, Guimarães RLFP, Lundberg M, et al. A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci. Genome Res. 2022;32(4):656-670.
32. Chen JM, Chuzhanova N, Stenson PD, Férec C, Cooper DN. Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions. Hum Mutat. 2005;26(4):362-373.
33. Elliott B, Richardson C, Jasin M. Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Mol Cell. 2005;17(6):885-894.
34. Mao YS, Zhang B, Spector DL. Biogenesis and function of nuclear bodies. Trends Genet. 2011;27(8):295-306.
35. Brown DD, Gurdon JB. Absence of ribosomal RNA synthesis in the anucleolate mutant of Xenopus laevis. Proc Natl Acad Sci U S A. 1964;51(1):139-146.
36. Sakai K, Ohta T, Minoshima S, et al. Human ribosomal RNA gene cluster: identification of the proximal end containing a novel tandem repeat sequence. Genomics. 1995;26(3):521-526.
37. Baranello L, Kouzine F, Wojtowicz D, et al. DNA break mapping reveals topoisomerase II activity genome-wide. Int J Mol Sci. 2014;15(7):13111-13122.
38. Crosetto N, Mitra A, Silva MJ, et al. Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing. Nat Methods. 2013;10(4):361-365.
39. Hutchins AP, Pei D. Transposable elements at the center of the crossroads between embryogenesis, embryonic stem cells, reprogramming, and long non-coding RNAs. Sci Bull (Beijing). 2015;60(20):1722-1733.
40. Wu K, Fan D, Zhao H, et al. Dynamics of histone acetylation during human early embryogenesis. Cell Discov. 2023;9(1):29.
41. Tumbar T, Belmont AS. Interphase movements of a DNA chromosome region modulated by VP16 transcriptional activator. Nat Cell Biol. 2001;3(2):134-139.
42. Dietzel S, Schiebel K, Little G, et al. The 3D positioning of ANT2 and ANT3 genes within female X chromosome territories correlates with gene activity. Exp Cell Res. 1999;252(2):363-375.
43. Wang H, Xu X, Nguyen CM, et al. CRISPR-mediated programmable 3D genome positioning and nuclear organization. Cell. 2018;175(5):1405-1417.e14.
44. Zink D, Amaral MD, Englmann A, et al. Transcription-dependent spatial arrangements of CFTR and adjacent genes in human cell nuclei. J Cell Biol. 2004;166(6):815-825.
45. Iborra FJ, Pombo A, Jackson DA, Cook PR. Active RNA polymerases are localized within discrete transcription "factories’ in human nuclei. J Cell Sci. 1996;109 ( Pt 6)(6):1427-1436.
46. de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990;347(6293):558-561.
47. de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300(5894):765-767.
48. Ortiz de Mendíbil I, Vizmanos JL, Novo FJ. Signatures of selection in fusion transcripts resulting from chromosomal translocations in human cancer. PLoS One. 2009;4(3):e4805.
49. Frenkel-Morgenstern M, Valencia A. Novel domain combinations in proteins encoded by chimeric transcripts. Bioinformatics. 2012;28(12):i67-74.
50. Shugay M, Ortiz de Mendíbil I, Vizmanos JL, Novo FJ. Genomic hallmarks of genes involved in chromosomal translocations in hematological cancer. PLoS Comput Biol. 2012;8(12):e1002797.
51. Wilhelm A, Marschalek R. The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11). Oncogene. 2021;40(42):6093-6102.
52. Bueno C, Calero-Nieto FJ, Wang X, et al. Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions. Haematologica. 2019;104(6):1189-1201.
53. Küppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20(40):5580-5594.
54. Cauwelier B, Dastugue N, Cools J, et al. Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbeta locus rearrangements and putative new T-cell oncogenes. Leukemia. 2006;20(7):1238-1244
55. Matharu NK, Ahanger SH. Chromatin insulators and topological domains: Adding new dimensions to 3D genome architecture. Genes (Basel). 2015;6(3):790-811.
56. Gröschel S, Sanders MA, Hoogenboezem R, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014;157(2):369-381.