The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: Prognostic implications and current clinical strategies

Blood Cancer Journal

Volumn 2, Issue 9, 2012, Pages

  Kalff, A ^a   Spencer, A ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

FGFR3; MMSET; multiple myeloma; t(4; 14); translocation

Indexed keywords

1 TERT BUTYL 3 [6 (3,5 DIMETHOXYPHENYL) 2 (4 DIETHYLAMINOBUTYLAMINO)PYRIDO[2,3 D]PYRIMIDIN 7 YL]UREA; 3 [4 METHYL 2 (2 OXO 3 INDOLINYLMETHYLIDENYL) 3 PYRROLYL]PROPIONIC ACID; BIBF 1000; BORTEZOMIB; CISPLATIN; CYCLOPHOSPHAMIDE; DEACETYLASE INHIBITOR; DEXAMETHASONE; DOVITINIB; DOXORUBICIN; ENZYME INHIBITOR; ETOPOSIDE; FIBROBLAST GROWTH FACTOR RECEPTOR 3; FIBROBLAST GROWTH FACTOR RECEPTOR 3 INHIBITOR; FLUDARABINE; IMMUNOGLOBULIN HEAVY CHAIN; IMMUNOMODULATING AGENT; LENALIDOMIDE; MELPHALAN; MIDOSTAURIN; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY R3; PREDNISONE; PRO 001; PROTEASOME INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; THALIDOMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINCRISTINE;

ALLOGENEIC STEM CELL TRANSPLANTATION; ANTINEOPLASTIC ACTIVITY; CANCER GROWTH; CANCER REGRESSION; CANCER RESISTANCE; CARCINOGENESIS; CHROMOSOME 14Q; CHROMOSOME TRANSLOCATION 4; CONTINUOUS INFUSION; CYTOGENETICS; DRUG EFFICACY; DRUG POTENTIATION; GENE DELETION; GENE DUPLICATION; GENE MUTATION; GENE OVEREXPRESSION; HIGH RISK PATIENT; HUMAN; MULTIPLE MYELOMA; NONHUMAN; OVERALL SURVIVAL; PERSONALIZED MEDICINE; PROGNOSIS; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN INDUCTION; RECEPTOR UPREGULATION; REVIEW; TREATMENT OUTCOME;

EID: 84871074734     PISSN: None     EISSN: 20445385     Source Type: Journal    
DOI: 10.1038/bcj.2012.37     Document Type: Review

References (71)

1. Katzel JA, Hari P, Vesole DH. Multiple myeloma: charging toward a bright future. CA Cancer J Clin 2007; 57: 301-318.
2. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516-2520.
3. Deininger MW, Druker BJ. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev 2003; 55: 401-423.
4. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005; 106: 296-303.
5. 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: 4798-4805.
6. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23: 2210-2221.
7. Stewart AK, Bergsagel PL, Greipp PR, Dispenzieri A, Gertz MA, Hayman SR et al. A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 2007; 21: 529-534.
8. Chng WJ, Van Wier SA, Ahmann GJ, Winkler JM, Jalal SM, Bergsagel PL et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 2005; 106: 2156-2161.
9. Chng WJ, Winkler JM, Greipp PR, Jalal SM, Bergsagel PL, Chesi M et al. Ploidy status rarely changes in myeloma patients at disease progression. Leuk Res 2006; 30: 266-271.
10. Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 2004; 64: 1546-1558.
11. Nahi H, Sutlu T, Jansson M, Alici E, Gahrton G. Clinical impact of chromosomal aberrations in multiple myeloma. J Intern Med 2011; 269: 137-147.
12. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002; 99: 2185-2191.
13. Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106: 2837-2840.
14. Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 2002; 100: 1579-1583.
15. Shaughnessy Jr J, Gabrea A, Qi Y, Brents L, Zhan F, Tian E et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 2001; 98: 217-223.
16. Boersma-Vreugdenhil GR, Kuipers J, Van Stralen E, Peeters T, Michaux L, Hagemeijer A et al. The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB: a molecular and genetic analysis of the chromosomal breakpoint. Br J Haematol 2004; 126: 355-363.
17. Avet-Loiseau H, Gerson F, Magrangeas F, Minvielle S, Harousseau J, Bataille R. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001; 98: 3082-3086.
18. Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997; 16: 260-264.
19. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020-2028.
20. Chng WJ, Kumar S, VanWier S, Ahmann G, Price-Troska T, Henderson K et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 2007; 67: 2982-2989.
21. Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 2010; 28: 4630-4634.
22. 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: 3489-3495.
23. Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006; 108: 1724-1732.
24. Reece D, Song KW, Fu T, Roland B, Chang H, Horsman DE et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 2009; 114: 522-525.
25. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906-917.
26. Richelda R, Ronchetti D, Baldini L, Cro L, Viggiano L, Marzella R et al. A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood 1997; 90: 4062-4070.
27. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998; 92: 3025-3034.
28. Fonseca R, Oken MM, Greipp PR. Eastern Cooperative Oncology Group Myeloma Group. The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance. Blood 2001; 98: 1271-1272.
29. Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, Garcia-Sanz R et al. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res 2011; 17: 1692-1700.
30. Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy Jr. J. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 2003; 101: 2374-2376.
31. Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 2005; 105: 4060-4069.
32. Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011; 117: 211-220.
33. Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 2011; 470: 124-128.
34. Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV et al. The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res 2011; 17: 2919-2933.
35. Intini D, Baldini L, Fabris S, Lombardi L, Ciceri G, Maiolo AT et al. Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14). Br J Haematol 2001; 114: 362-364.
36. Ronchetti D, Greco A, Compasso S, Colombo G, Dell'Era P, Otsuki T et al. Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations. Oncogene 2001; 20: 3553-3562.
37. Onwuazor ON, Wen XY, Wang DY, Zhuang L, Masih-Khan E, Claudio J et al. Mutation, SNP, and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients. Blood 2003; 102: 772-773.
38. Vatsveen TK, Brenne AT, Dai HY, Waage A, Sundan A, Borset M. FGFR3 is expressed and is important for survival in INA-6, a human myeloma cell line without a t(4;14). Eur J Haematol 2009; 83: 471-476.
39. Quintero-Rivera F, El-Sabbagh Badr R, Rao PN. FGFR3 amplification in the absence of IGH@-FGFR3 fusion t(4;14) in myeloma. Cancer Genet Cytogenet 2009; 195: 92-93.
40. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010; 10: 116-129.
41. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. J Biol Chem 2006; 281: 15694-15700.
42. Courjal F, Cuny M, Simony-Lafontaine J, Louason G, Speiser P, Zeillinger R et al. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res 1997; 57: 4360-4367.
43. Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C et al. Drugsensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci USA 2008; 105: 8713-8717.
44. Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999; 23: 18-20.
45. Munro NP, Knowles MA. Fibroblast growth factors and their receptors in transitional cell carcinoma. J Urol 2003; 169: 675-682.
46. Otsuki T, Yamada O, Yata K, Sakaguchi H, Kurebayashi J, Nakazawa N et al. Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation. Int J Oncol 1999; 15: 1205-1212.
47. Li Z, Zhu YX, Plowright EE, Bergsagel PL, Chesi M, Patterson B et al. The myelomaassociated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 2001; 97: 2413-2419.
48. Qing J, Du X, Chen Y, Chan P, Li H, Wu P et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest 2009; 119: 1216-1229.
49. Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica 2010; 95: 1150-1157.
50. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412-3420.
51. Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 2004; 125: 64-68.
52. Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 2001; 15: 981-986.
53. Loiseau HA, Attal M, Moreau P, Charbonnel C, Garban F, Harousseau J et al. A comprehensive analysis of cytogenetic abnormalities in myeloma: Results of the FISH analysis of 1000 patients enrolled in the IFM99 trials. Blood 2005; 106: 622.
54. Karlin L, Soulier J, Chandesris O, Choquet S, Belhadj K, Macro M et al. Clinical and biological features of t(4;14) multiple myeloma: a prospective study. Leuk Lymphoma 2011; 52: 238-246.
55. Jaksic W, Trudel S, Chang H, Trieu Y, Qi X, Mikhael J et al. Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol 2005; 23: 7069-7073.
56. Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 2010; 24: 623-628.
57. Chang H, Trieu Y, Qi X, Xu W, Stewart KA, Reece D. Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 2007; 31: 779-782.
58. Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol 2008; 140: 625-634.
59. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol 2007; 138: 176-185.
60. Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009; 84: 1095-1110.
61. Schilling G, Hansen T, Shimoni A, Zabelina T, Perez-Simon JA, Gutierrez NC et al. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia 2008; 22: 1250-1255.
62. Dawson MA, Opat SS, Taouk Y, Donovan M, Zammit M, Monaghan K et al. Clinical and immunohistochemical features associated with a response to bortezomib in patients with multiple myeloma. Clin Cancer Res 2009; 15: 714-722.
63. Paterson JL, Li Z, Wen XY, Masih-Khan E, Chang H, Pollett JB et al. Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol 2004; 124: 595-603.
64. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005; 105: 2941-2948.
65. Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 2004; 103: 3521-3528.
66. Trudel S, Stewart AK, Rom E, Wei E, Li ZH, Kotzer S et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 2006; 107: 4039-4046.
67. Xin X, Abrams TJ, Hollenbach PW, Rendahl KG, Tang Y, Oei YA et al. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin Cancer Res 2006; 12: 4908-4915.
68. Bisping G, Wenning D, Kropff M, Gustavus D, Muller-Tidow C, Stelljes M et al. Bortezomib, dexamethasone, and fibroblast growth factor receptor 3-specific tyrosine kinase inhibitor in t(4;14) myeloma. Clin Cancer Res 2009; 15: 520-531.
69. Sharkey J, Khong T, Spencer A. PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. Blood 2007; 109: 1712-1719.
70. Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L et al. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 2005; 11: 3633-3641.
71. Sarker D, Molife R, Evans TR, Hardie M, Marriott C, Butzberger-Zimmerli P et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res 2008; 14: 2075-2081.