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Molekulární patofyziologie ribozomopatií – onemocnění s narušenou funkcí ribozomů


Authors: O. Jahoda 1;  S. Kureková 1;  K. Hlušičková Kapraľová 1;  D. Pospíšilová 2;  M. Horváthová 1
Authors‘ workplace: Ústav biologie, LF UP, Olomouc 2 Dětská klinika LF UP a FN Olomouc 1
Published in: Transfuze Hematol. dnes,29, 2023, No. 2, p. 106-116.
Category: Review/Educational Papers
doi: https://doi.org/10.48095/cctahd2023prolekare.cz4

Overview

Ribosomes are cellular structures responsible for protein synthesis. They are formed during a complex process called ribosome biogenesis. Congenital ribosomopathies are a heterogeneous group of diseases caused by genetic abnormalities that disrupt ribosome biogenesis and function with causative mutations affecting genes encoding for ribosomal proteins or other factors involved in ribosome biogenesis. A hallmark of congenital ribosomopathies is tissue-specific damage and an increased risk of cancer development. In addition, recent research has revealed that somatic mutations in genes for ribosomal proteins are also clinically relevant as they are involved in the process of malignant transformation. In this review article, we describe the pathophysiological effects of ribosome dysfunction at the cellular and molecular level, as well as possible mechanisms promoting oncogenesis. The article also discusses current treatment of ribosomopathies and presents new therapeutic options.

Keywords:

ribosomopathies – ribosome biogenesis – translation – Diamond-Blackfan anaemia


Sources

1. Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999; 21 (2): 169–175.

2. Kampen KR, Sulima SO, Vereecke S, De Keersmaecker K. Hallmarks of ribosomopathies. Nucleic Acids Res. 2020; 48 (3): 1013–1028.

3. Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010; 115 (16): 3196–3205.

4. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012; 119 (16): 3815–3819.

5. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010; 116 (19): 3715–3723.

6. Sankaran VG, Ghazvinian R, Do R, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012; 122 (7): 2439–2443.

7. Ludwig LS, Gazda HT, Eng JC, et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med. 2014; 20 (7): 748–753.

8. Gripp KW, Curry C, Olney AH, et al. Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am J Med Genet A. 2014; 164A (9): 2240–2249.

9. Lee PY. Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediatr. 2018; 6: 282.

10. Kim AR, Ulirsch JC, Wilmes S, et al. Functional selectivity in cytokine signaling revealed through a pathogenic EPO mutation. Cell. 2017; 168 (6): 1053–1064.e15.

11. Da Costa L, Leblanc T, Mohandas N. Diamond-Blackfan anemia. Blood. 2020; 136 (11): 1262–1273.

12. AlSabbagh MM. Dyskeratosis congenita: a literature review. J Dtsch Dermatol Ges. 2020; 18 (9): 943–967.

13. Savage SA, Niewisch MR Dyskeratosis congenita and related telomere biology disorders. GeneReviews® [Internet] 2009 [updated 2022].

14. Venturi G, Montanaro L. How altered ribosome production can cause or contribute to human disease: the spectrum of ribosomopathies. Cells. 2020; 9 (10): 2300.

15. Garus A, Autexier C. Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance. RNA. 2021; 27 (12): 1441–1458.

16. Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009; 23 (2): 233–248.

17. Dale DC, Bolyard AA, Shannon JA, et al. Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor. Blood Adv. 2022; 6 (13): 3861–3869.

18. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003; 33 (1): 97–101.

19. Nelson A, Myers K. Shwachman-Diamond Syndrome. GeneReviews®[Internet] 2008 [updated 2018].

20. Sulisalo T, Francomano CA, Sistonen P, et al. High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families. Genomics. 1994; 20 (3): 347–353.

21. Riley P Jr, Weiner DS, Leighley B, et al. Cartilage hair hypoplasia: characteristics and orthopaedic manifestations. J Child Orthop. 2015; 9 (2): 145–152.

22. Ridanpää M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001; 104 (2): 195–203.

23. Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet. 2007; 81 (3): 519–529.

24. Dauwerse JG, Dixon J, Seland S, et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet. 2011; 43 (1): 20–22.

25. Ajore R, Raiser D, McConkey M, et al. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol Med. 2017; 9 (4): 498–507.

26. Amsterdam A, Sadler KC, Lai K, et al. Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol. 2004; 2 (5): E139.

27. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022; 36 (7): 1703–1719.

28. Scharenberg C, Giai V, Pellagatti A, et al. Progression in patients with low- and intermediate-1-risk del (5q) myelodysplastic syndromes is predicted by a limited subset of mutations. Haematologica. 2017; 102 (3): 498–508.

29. Yang K, Yang J, Yi J. Nucleolar Stress: hallmarks, sensing mechanism and diseases. Cell Stress. 2018; 2 (6): 125–140.

30. Michael D, Oren M. The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol. 2003; 13 (1): 49–58.

31. Donati G, Peddigari S, Mercer CA, Thomas G. 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint. Cell Rep. 2013; 4 (1): 87–98.

32. Sloan KE, Bohnsack MT, Watkins NJ. The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep. 2013; 5 (1): 237–247.

33. Farley-Barnes KI, Ogawa LM, Baserga SJ. Ribosomopathies: old concepts, new controversies. Trends Genet. 2019; 35 (10): 754–767.

34. Khajuria RK, Munschauer M, Ulirsch JC et al. Ribosome levels selectively regulate translation and lineage commitment in human hematopoiesis. Cell. 2018; 173 (1): 90–103.e19.

35. Trainor CD, Mas C, Archambault P, Di Lello P, Omichinski JG. GATA-1 associates with and inhibits p53. Blood. 2009; 114 (1): 165–173.

36. Gastou M, Rio S, Dussiot M, et al. The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70. Blood Adv. 2017; 1 (22): 1959–1976.

37. Horos R, Ijspeert H, Pospisilova D, et al. Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts. Blood. 2012; 119 (1): 262–272.

38. Ambekar C, Das B, Yeger H, Dror Y. SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth. Pediatr Blood Cancer. 2010; 55 (6): 1138–1144.

39. Kapralova K, Jahoda O, Koralkova P, et al. Oxidative DNA damage, inflammatory signature, and altered erythrocytes properties in Diamond-Blackfan anemia. Int J Mol Sci. 2020; 21 (24): 9652.

40. Sulima SO, Kampen KR, Vereecke S, et al. Ribosomal lesions promote oncogenic mutagenesis. Cancer Res. 2019; 79 (2): 320–327.

41. Pereboeva L, Westin E, Patel T, et al. DNA damage responses and oxidative stress in dyskeratosis congenita. PLoS One. 2013; 8 (10): e76 473.

42. Rio S, Gastou M, Karboul N, et al. Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1. Blood. 2019; 133 (12): 1358–1370.

43. Zambetti NA, Ping Z, Chen S, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016; 19 (5): 613–627.

44. Kampen KR, Sulima SO, Verbelen B, et al. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL. Leukemia. 2019; 33 (2): 319–332.

45. Girardi T, Vereecke S, Sulima SO, et al. The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling. Leukemia. 2018; 32 (3): 809–819.

46. Oršolić I, Bursać S, Jurada D, et al. Cancer-associated mutations in the ribosomal protein L5 gene dysregulate the HDM2/p53-mediated ribosome biogenesis checkpoint. Oncogene. 2020; 39 (17): 3443–3457.

47. Liao JM, Zhou X, Gatignol A, Lu H. Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex. Oncogene. 2014; 33 (41): 4916–4923.

48. Zhou X, Hao Q, Liao JM, Liao P, Lu H. Ribosomal protein S14 negatively regulates c-Myc activity. J Biol Chem. 2013; 288 (30): 21793–21801.

49. Dameshek W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and „hypoplastic“ leukemia have in common? Blood. 1967; 30 (2): 251–254.

50. Xia J, Miller CA, Baty J, et al. Somatic mutations and clonal hematopoiesis in congenital neutropenia. Blood. 2018; 131 (4): 408–416.

51. Pospíšilová D. Vzácné anémie ze skupiny vrozených syndromů selhání kostní dřeně. Vnitr Lek. 2018; 64 (5): 488–500.

52. Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008; 142 (6): 859–876.

53. Kimball SR, Jefferson LS. New functions for amino acids: effects on gene transcription and translation. Am J Clin Nutr. 2006; 83 (2): 500S–507S.

54. Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R. Successful treatment of a Diamond-Blackfan anemia patient with amino acid leucine. Haematologica. 2007; 92 (5): e66–e67.

55. Vlachos A, Atsidaftos E, Lababidi ML, et al. L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry. Pediatr Blood Cancer. 2020; 67 (12): e28748.

56. Joyce CE, Saadatpour A, Ruiz-Gutierrez M, et al. TGFb signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond Syndrome. J Clin Invest. 2019; 129 (9): 3821–3826.

57. Ge J, Apicella M, Mills JA, et al. Dysregulation of the transforming growth factor b pathway in induced pluripotent stem cells generated from patients with Diamond Blackfan anemia. PLoS One. 2015; 10 (8): e0134878.

58. Brancaleoni V, Nava I, Delbini P, Duca L, Motta I. Activin receptor-ligand trap for the treatment of b-thalassemia: a serendipitous discovery. Mediterr J Hematol Infect Dis. 2020; 12 (1): e2020 075.

59. Ear J, Huang H, Wilson T, et al. RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1. Blood. 2015; 126 (7): 880–890.

60. Bewersdorf JP, Zeidan AM. Transforming growth factor (TGF) -b pathway as a therapeutic target in lower risk myelodysplastic syndromes. Leukemia. 2019; 33 (6): 1303–1312.

61. Taylor AM, Macari ER, Chan IT, et al. Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia. Sci Transl Med. 2020; 12 (566): eabb5831.

62. Macari ER, Taylor AM, Raiser D, et al. Calmodulin inhibition rescues DBA models with ribosomal protein deficiency through reduction of RSK signaling. Blood. 2012; 120: 2214–2224.

63. Orgebin E, Lamoureux F, Isidor B, et al. Ribosomopathies: new therapeutic perspectives. Cells. 2020; 9 (9): 2080.

64. Hamaguchi I, Ooka A, Brun A, Richter J, Dahl N, Karlsson S. Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia. Blood. 2002; 100 (8): 2724–2731.

65. Aspesi A, Monteleone V, Betti M, et al. Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy. Sci Rep. 2017; 7 (1): 12010.

66. Liu Y, Dahl M, Debnath S, et al. Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector. Haematologica. 2022; 107 (2): 446–456.

67. Jaako P, Debnath S, Olsson K, et al. Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia. Haematologica. 2014; 99 (12): 1792–1798.

68. Debnath S, Jaako P, Siva K, et al. Lentiviral vectors with cellular promoters correct anemia and lethal bone marrow failure in a mouse model for Diamond-Blackfan anemia. Mol Ther. 2017; 25 (8): 1805–1814.

69. Skvarova Kramarzova K, Osborn MJ, Webber BR, et al. CRISPR/Cas9-mediated correction of the FANCD1 gene in primary patient cells. Int J Mol Sci. 2017; 18 (6): 1269.

Labels
Haematology Internal medicine Clinical oncology

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