Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Multiple myeloma gammopathies

Genome instability in multiple myeloma

Leukemia volume 34, pages 2887–2897 (2020)Cite this article

Subjects

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal proliferation of plasma cells and a heterogenous genomic landscape. Copy number and structural changes due to chromosomal instability (CIN) are common features of MM. In this review, we describe how primary and secondary genetic events caused by CIN can contribute to increased instability across the genome of malignant plasma cells; with a focus on specific driver genomic events, and how they interfere with cell-cycle checkpoints, to prompt accelerated proliferation. We also provide insight into other forms of CIN, such as chromothripsis and chromoplexy. We evaluate how the tumor microenvironment can contribute to a further increase in chromosomal instability in myeloma cells. Lastly, we highlight the role of certain mutational signatures in leading to high mutation rate and genome instability in certain MM patients. We suggest that assessing CIN in MM and its precursors states may help improve predicting the risk of progression to symptomatic disease and relapse and identifying future therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Recurrent genetic alterations in multiple myeloma.
Fig. 2: Summary of chromosomal rearrangements in B-cells and aberrant translocation events in multiple myeloma.
Fig. 3: Mechanisms of chromothripsis and chromoplexy in cancer cells.
Fig. 4: Tumor-microenvironment contribution to genome instability of malignant cells.

Similar content being viewed by others

References

  1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046–60.

    CAS  PubMed  Google Scholar 

  2. Howlader Nea. SEER cancer statistics review. SEER. 1975–2013. https://seer.cancer.gov/csr/1975_2013/.

  3. Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017;14:100–13.

    CAS  PubMed  Google Scholar 

  4. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bakhoum SF, Landau DA. Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb Perspect Med. 2017;7:a029611. https://doi.org/10.1101/cshperspect.a029611.

  6. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.

    CAS  PubMed  Google Scholar 

  7. Sansregret L, Vanhaesebroeck B, Swanton C. Determinants and clinical implications of chromosomal instability in cancer. Nat Rev Clin Oncol. 2018;15:139–50.

    CAS  PubMed  Google Scholar 

  8. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in human cancers. Nature. 1998;396:643–9.

    CAS  PubMed  Google Scholar 

  9. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45:1127.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Roschke AV, Rozenblum E. Multi-layered cancer chromosomal instability phenotype. Front Oncol. 2013;3:302.

    PubMed  PubMed Central  Google Scholar 

  11. Thompson LL, Jeusset LM, Lepage CC, McManus KA-O. Evolving therapeutic strategies to exploit chromosome instability in cancer. Cancers. 2017;9:151. https://doi.org/10.3390/cancers9110151.

  12. Casimiro MC, Pestell RG. Cyclin d1 induces chromosomal instability. Oncotarget. 2012;3:224–5.

    PubMed  PubMed Central  Google Scholar 

  13. Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature. 2009;460:278–82. (1476-4687 (Electronic))

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bakhoum SF, Genovese G, Compton DA. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol. 2009;19:1937–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC, Shaikh N, et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 2013;494:492–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012;482:53–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Decaux O, Lode L, Magrangeas F, Charbonnel C, Gouraud W, Jezequel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2008;26:4798–805.

    CAS  PubMed  Google Scholar 

  18. Chung TH, Mulligan G, Fonseca R, Chng WJ. A novel measure of chromosome instability can account for prognostic difference in multiple myeloma. PLoS ONE. 2013;8.

  19. Boveri T. Über mehrpolige Mitosen als Mittel zur Analyse des Zellkerns [On multipolar mitosis as a means of analysis of the cell nucleus]. Verh Phys Med Ges Wurzbg. 1903;35:67–90.

    Google Scholar 

  20. Drach J, Schuster J, Nowotny H, Angerler J, Rosenthal F, Fiegl M, et al. Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res. 1995;55:3854–9.

    CAS  PubMed  Google Scholar 

  21. Maura F, Bolli N, Angelopoulos N, Dawson KJ, Leongamornlert D, Martincorena I, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun. 2019;10:3835.

    PubMed  PubMed Central  Google Scholar 

  22. Bustoros M, Sklavenitis-Pistofidis R, Park J, Redd R, Zhitomirsky B, Dunford AJ, et al. Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression. J Clin Oncol. 2020:Jco2000437. [Epub ahead of print]

  23. Mei J, Zhai Y, Li H, Li F, Zhou X, Song P, et al. Prognostic impact of hyperdiploidy in multiple myeloma patients with high-risk cytogenetics: a pilot study in China. J Cancer Res Clin Oncol. 2018;144:2263–73.

    CAS  PubMed  Google Scholar 

  24. Sheltzer JM, Ko JH, Replogle JM, Habibe Burgos NC, Chung ES, Meehl CM, et al. Single-chromosome gains commonly function as tumor suppressors. Cancer Cell. 2017;31:240–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.

    CAS  PubMed  Google Scholar 

  26. Oh S, Koo Dh Fau - Kwon M-J, Kwon Mj Fau - Kim K, Kim K, Fau - Suh C, Suh C, et al. Chromosome 13 deletion and hypodiploidy on conventional cytogenetics are robust prognostic factors in Korean multiple myeloma patients: web-based multicenter registry study. Ann Hematol. 2014;93:1353–61.

    CAS  PubMed  Google Scholar 

  27. Wu P, Li T, Li R, Jia L, Zhu P, Liu Y, et al. 3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations. Nat Commun. 2017;8:1937.

    PubMed  PubMed Central  Google Scholar 

  28. Pope BD, Ryba T, Dileep V, Yue F, Wu W, Denas O, et al. Topologically associating domains are stable units of replication-timing regulation. Nature. 2014;515:402.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116:e56–65.

    CAS  PubMed  Google Scholar 

  30. Pawlyn C, Morgan GJ. Evolutionary biology of high-risk multiple myeloma. Nat Rev Cancer. 2017;17:543.

    CAS  PubMed  Google Scholar 

  31. Chang H, Qi X, Trieu Y, Xu W, Reader JC, Ning Y, et al. Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation. Br J Haematol. 2006;135:486–91.

    CAS  PubMed  Google Scholar 

  32. Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33:3911–20.

    CAS  PubMed  Google Scholar 

  33. Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B. Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood. 1998;91:1732–41.

    CAS  PubMed  Google Scholar 

  34. Maganti HB, Jrade H, Cafariello C, Manias Rothberg JL, Porter CJ, Yockell-Lelièvre J, et al. Targeting the MTF2–MDM2 axis sensitizes refractory acute myeloid leukemia to chemotherapy. Cancer Discov. 2018;8:1376–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109:3489–95.

    CAS  PubMed  Google Scholar 

  36. Avet-Loiseau H, Li JY, Morineau N, Facon T, Brigaudeau C, Harousseau JL, et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood. 1999;94:2583–9.

    CAS  PubMed  Google Scholar 

  37. Chavan SS, He J, Tytarenko R, Deshpande S, Patel P, Bailey M, et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J. 2017;7:e535-e.

    Google Scholar 

  38. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33:159–70.

    CAS  PubMed  Google Scholar 

  39. Lenz G, Pasqualucci L, Klapper W, Klein U, Silva NSD, Zha S, et al. Malignant Lymphomas. 1st edn. Berlin/Boston: De Gruyter; 2016.

  40. Jung D, Giallourakis C, Mostoslavsky R, Alt FW. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol. 2006;24:541–70.

    CAS  PubMed  Google Scholar 

  41. Lieber MR, Yu K, Raghavan SC. Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair. 2006;5:1234–45.

    CAS  PubMed  Google Scholar 

  42. Max EE. Immunoglobulins: molecular genetics. In: Paul WE, editor. Philadelphia, PA: Lippincott-Raven; 1999.

  43. Ramiro A, Reina San-Martin B, McBride K, Jankovic M, Barreto V, Nussenzweig A, et al. The role of activation-induced deaminase in antibody diversification and chromosome translocations. Adv Immunol. 2007;94:75–107.

    CAS  PubMed  Google Scholar 

  44. Fenton JA, Pratt G, Rawstron AC, Morgan GJ. Isotype class switching and the pathogenesis of multiple myeloma. Hematol Oncol.2002;20:75–85.

    CAS  PubMed  Google Scholar 

  45. Nishida K, Tamura A, Nakazawa N, Ueda Y, Abe T, Matsuda F, et al. The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood. 1997;90:526–34.

    CAS  PubMed  Google Scholar 

  46. Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013;97:313–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132:587–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008;8:976–90.

    CAS  PubMed  Google Scholar 

  49. Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Walker BA-O, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.

    PubMed  Google Scholar 

  51. Bretones G, Delgado MD, Leon J. Myc and cell cycle control. Biochim Biophys Acta. 2015;1849:506–16.

    CAS  PubMed  Google Scholar 

  52. Felsher DW, Bishop JM. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci USA. 1999;96:3940–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kuzyk A, Mai S. c-MYC-induced genomic instability. Cold Spring Harb Perspect Med. 2014;4:a014373.

    PubMed  PubMed Central  Google Scholar 

  54. Kumari A, Folk WP, Sakamuro D. The dual roles of MYC in genomic instability and cancer chemoresistance. Genes. 2017;8:158. https://doi.org/10.3390/genes8060158.

  55. Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and kataegis induced by telomere crisis. Cell. 2015;163:1641–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154:47–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang C-Z, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522:179.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood. 2011;118:675–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Rustad EH, Yellapantula VD, Glodzik D, Maclachlan KH, Diamond B, Boyle EM, et al. Revealing the impact of recurrent and rare structural variants in multiple myeloma. 2019. https://www.biorxiv.org/content/10.1101/2019.12.18.881086v1.full.

  61. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P, et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res 1998;58:3974–85.

    CAS  PubMed  Google Scholar 

  63. Nigg EA. Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer. 2002;2:815.

    CAS  PubMed  Google Scholar 

  64. Uetake Y, Sluder G. Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a “tetraploidy checkpoint”. J Cell Biol. 2004;165:609–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS. Spindle multipolarity is prevented by centrosomal clustering. Science. 2005;307:127–9.

    CAS  PubMed  Google Scholar 

  66. Chng WJ, Ahmann GJ, Henderson K, Santana-Davila R, Greipp PR, Gertz MA, et al. Clinical implication of centrosome amplification in plasma cell neoplasm. Blood. 2006;107:3669–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dutertre S, Descamps S, Prigent C. On the role of aurora-A in centrosome function. Oncogene. 2002;21:6175.

    CAS  PubMed  Google Scholar 

  68. Shi Y, Reiman T, Li W, Maxwell CA, Sen S, Pilarski L, et al. Targeting aurora kinases as therapy in multiple myeloma. Blood. 2007;109:3915–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Carmena M, Earnshaw WC. The cellular geography of Aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842.

    CAS  PubMed  Google Scholar 

  70. Zhou H, Kuang J, Zhong L, Kuo W-L, Gray J, Sahin A, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998;20:189.

    CAS  PubMed  Google Scholar 

  71. Hose D, Reme T, Meissner T, Moreaux J, Seckinger A, Lewis J, et al. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood. 2009;113:4331–40.

    CAS  PubMed  Google Scholar 

  72. Shaughnessy JD,Jr., Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:2276–84.

    CAS  PubMed  Google Scholar 

  73. Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol. 2010;20:R285–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J,Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kornmann M, Danenberg KD, Arber N, Beger HG, Danenberg PV, Korc M. Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes. Cancer Res. 1999;59:3505–11.

    CAS  PubMed  Google Scholar 

  76. Casimiro MC, Pestell RG. Cyclin d1 induces chromosomal instability. Oncotarget. 2012;3:224–45.

    PubMed  PubMed Central  Google Scholar 

  77. Vose JM. Mantle cell lymphoma: 2015 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2015;90:739–45.

    CAS  PubMed  Google Scholar 

  78. Saavedra HI, Fukasawa K, Conn CW, Stambrook PJ. MAPK mediates RAS-induced chromosome instability. J Biol Chem. 1999;274:38083–90.

    CAS  PubMed  Google Scholar 

  79. Hanel W, Moll UM. Links between mutant p53 and genomic instability. J Cell Biochem. 2012;113:433–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, et al. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Investig. 2012;122:833–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Rossi A, Voigtlaender M, Janjetovic S, Thiele B, Alawi M, Marz M, et al. Mutational landscape reflects the biological continuum of plasma cell dyscrasias. Blood Cancer J. 2017;7:e537.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Reynolds TY, Rockwell S, Glazer PM. Genetic instability induced by the tumor microenvironment. Cancer Res. 1996;56:5754–7.

    CAS  PubMed  Google Scholar 

  83. Li CY, Little JB, Hu K, Zhang W, Zhang L, Dewhirst MW, et al. Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures. Cancer Res 2001;61:428–32.

    CAS  PubMed  Google Scholar 

  84. Paquette B, Little JB. In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays. Cancer Res. 1994;54:3173–8.

    CAS  PubMed  Google Scholar 

  85. Semenza GL. Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2010;2:336–61.

    CAS  PubMed  Google Scholar 

  86. Azab AK, Hu J, Quang P, Azab F, Pitsillides C, Awwad R, et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood. 2012;119:5782–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bindra RS, Glazer PM. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res. 2005;569:75–85.

    CAS  PubMed  Google Scholar 

  88. Meynet O, Bénéteau M, Jacquin MA, Pradelli LA, Cornille A, Carles M, et al. Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis. Leukemia. 2011;26:1145.

    PubMed  Google Scholar 

  89. Fujiwara S, Kawano Y, Yuki H, Okuno Y, Nosaka K, Mitsuya H. et al. PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer. 2013;108:170–8.

    CAS  PubMed  Google Scholar 

  90. Varshavsky A. On the possibility of metabolic control of replicon “misfiring”: relationship to emergence of malignant phenotypes in mammalian cell lineages. Proc Natl Acad Sci USA. 1981;78:3673.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, et al. Genomic patterns of progression in smoldering multiple myeloma. Nat Commun. 2018;9:3363.

    PubMed  PubMed Central  Google Scholar 

  92. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Keenan TE, Burke KP, Van Allen EM. Genomic correlates of response to immune checkpoint blockade. Nat Med. 2019;25:389–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wienand K, Chapuy B, Stewart C, Dunford AJ, Wu D, Kim J, et al. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv. 2019;3:4065–80.

    PubMed  PubMed Central  Google Scholar 

  95. Chapuy B, Stewart C, Dunford AJ, Kim J, Wienand K, Kamburov A, et al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood. 2019;134:2369–82.

    PubMed  PubMed Central  Google Scholar 

  96. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K, et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149:979–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Maura F, Petljak M, Lionetti M, Cifola I, Liang W, Pinatel E, et al. Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia. 2018;32:1043–7.

    Google Scholar 

Download references

Acknowledgements

This review was supported in part by National Institutes of Health grant (NIH R01 CA 205954), German Society for Internal Medicine (DGIM), German Academic Scholarship Foundation, the Multiple Myeloma research Foundation (MMRF), and Leukemia and Lymphoma Society (LLS).

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Carl Jannes Neuse, Oliver C. Lomas, Yu Jia Shen, Mark Bustoros & Irene M. Ghobrial

  2. Department of Medicine A, Hematology and Oncology, Münster University Hospital, Münster, Germany

    Carl Jannes Neuse & Christoph Schliemann

  3. Service des Maladies du Sang, CHU Lille, Lille, France

    Salomon Manier

  4. Center for Prevention of Progression, Dana-Farber Cancer Institute, Boston, MA, USA

    Mark Bustoros & Irene M. Ghobrial

Authors
  1. Carl Jannes Neuse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver C. Lomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Schliemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Jia Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Salomon Manier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Bustoros
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irene M. Ghobrial
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mark Bustoros or Irene M. Ghobrial.

Ethics declarations

Conflict of interest

There was no commercial funding for this review. MB has advisory role and received Honoraria from Takeda and has received honoraria Dava Oncology. IMG has a consulting and advisory role with Celgene, Takeda, Bristol-Myers Squibb, Genentech, Janssen Pharmaceuticals, and Amgen, and has received research funding/honoraria from Celgene, Takeda, Bristol-Myers Squibb, Janssen Pharmaceuticals, and Amgen. The rest of the authors have no conflicts to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neuse, C.J., Lomas, O.C., Schliemann, C. et al. Genome instability in multiple myeloma. Leukemia 34, 2887–2897 (2020). https://doi.org/10.1038/s41375-020-0921-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0921-y

This article is cited by

Search

Advanced search

Quick links