Molecular Pathogenesis of Multiple Myeloma

Hematology/Oncology Clinics of North America

Volumn 21, Issue 6, 2007, Pages 985-1006

  Tonon, Giovanni ^a  

^a DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLINE; FIBROBLAST GROWTH FACTOR RECEPTOR 3; PROTEIN P18; PROTEIN P53; RETINOBLASTOMA PROTEIN; TRANSCRIPTION FACTOR MAF; TRANSCRIPTION FACTOR MAFB;

CANCER GENETICS; CHROMOSOME 13; CHROMOSOME TRANSLOCATION; DISEASE COURSE; GENE MUTATION; HUMAN; MOLECULAR GENETICS; MONOCLONAL IMMUNOGLOBULINEMIA; MULTIPLE MYELOMA; NONHUMAN; ONCOGENE MYC; ONCOGENE RAS; PATHOGENESIS; PRIORITY JOURNAL; PROGNOSIS; REVIEW;

CHROMOSOME ABERRATIONS; CHROMOSOMES, HUMAN, PAIR 13; CYCLINS; GENES, MYC; GENES, P53; HUMANS; MONOCLONAL GAMMOPATHIES, BENIGN; MULTIPLE MYELOMA;

EID: 35948984149     PISSN: 08898588     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.hoc.2007.08.004     Document Type: Review

References (153)

1. Mitsiades C.S., Mitsiades N., Munshi N.C., et al. Focus on multiple myeloma. Cancer Cell 6 5 (2004) 439-444
2. Kyle R.A., and Rajkumar S.V. Monoclonal gammopathies of undetermined significance: a review. Immunol Rev 194 (2003) 112-139
3. Kyle R.A., and Rajkumar S.V. Multiple myeloma. N Engl J Med 351 18 (2004) 1860-1873
4. Anderson K.C., Shaughnessy Jr. J.D., Barlogie B., et al. Multiple myeloma. Hematology Am Soc Hematol Educ Program (2002) 214-240
5. Kuehl W.M., and Bergsagel P.L. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2 3 (2002) 175-187
6. Richardson P.G., Barlogie B., Berenson J., et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 106 9 (2005) 2977-2981
7. Richardson P.G., Mitsiades C.S., Hideshima T., et al. Novel biological therapies for the treatment of multiple myeloma. Best Pract Res Clin Haematol 18 4 (2005) 619-634
8. Barlogie B., Shaughnessy J., Tricot G., et al. Treatment of multiple myeloma. Blood 103 1 (2004) 20-32
9. Bergsagel P.L., Kuehl W.M., Zhan F., et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106 1 (2005) 296-303
10. Carrasco D.R., Tonon G., Huang Y., et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9 4 (2006) 313-325
11. Zhan F., Huang Y., Colla S., et al. The molecular classification of multiple myeloma. Blood 108 6 (2006) 2020-2028
12. Smadja N.V., Fruchart C., Isnard F., et al. Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia 12 6 (1998) 960-969
13. Pui C.H., Relling M.V., and Downing J.R. Acute lymphoblastic leukemia. N Engl J Med 350 15 (2004) 1535-1548
14. Sawyer J.R., Waldron J.A., Jagannath S., et al. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 82 1 (1995) 41-49
15. Lai J.L., Zandecki M., Mary J.Y., et al. Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 85 9 (1995) 2490-2497
16. Smadja N.V., Bastard C., Brigaudeau C., et al. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 98 7 (2001) 2229-2238
17. Fonseca R., Debes-Marun C.S., Picken E.B., et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 102 7 (2003) 2562-2567
18. Chng W.J., Van Wier S.A., Ahmann G.J., et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 106 6 (2005) 2156-2161
19. Chng W.J., Winkler J.M., Greipp P.R., et al. Ploidy status rarely changes in myeloma patients at disease progression. Leuk Res 30 3 (2006) 266-271
20. Brunet J.P., Tamayo P., Golub T.R., et al. Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci U S A 101 12 (2004) 4164-4169
21. Bergsagel P.L., and Kuehl W.M. Chromosome translocations in multiple myeloma. Oncogene 20 40 (2001) 5611-5622
22. Bergsagel P.L., Chesi M., Nardini E., et al. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci U S A 93 24 (1996) 13931-13936
23. Debes-Marun C.S., Dewald G.W., Bryant S., et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia 17 2 (2003) 427-436
24. Seto M., Yamamoto K., Iida S., et al. Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation. Oncogene 7 7 (1992) 1401-1406
25. Chesi M., Bergsagel P.L., Brents L.A., et al. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88 2 (1996) 674-681
26. Akiyama N., Tsuruta H., Sasaki H., et al. Messenger RNA levels of five genes located at chromosome 11q13 in B-cell tumors with chromosome translocation t(11;14)(q13;q32). Cancer Res 54 2 (1994) 377-379
27. Kobayashi H., Saito H., Kitano K., et al. Overexpression of the PRAD1 oncogene in a patient with multiple myeloma and t(11;14)(q13;q32). Acta Haematol 94 4 (1995) 199-203
28. Gabrea A., Bergsagel P.L., Chesi M., et al. Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell. Mol Cell 3 1 (1999) 119-123
29. Shaughnessy Jr. J., Gabrea A., Qi Y., et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98 1 (2001) 217-223
30. Chesi M., Nardini E., Brents L.A., 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 16 3 (1997) 260-264
31. Richelda R., Ronchetti D., Baldini L., et al. A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood 90 10 (1997) 4062-4070
32. Chesi M., Nardini E., Lim R.S., et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92 9 (1998) 3025-3034
33. Chesi M., Brents L.A., Ely S.A., et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97 3 (2001) 729-736
34. Intini D., Baldini L., Fabris S., et al. Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14). Br J Haematol 114 2 (2001) 362-364
35. Chesi M., Bergsagel P.L., Shonukan O.O., et al. Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91 12 (1998) 4457-4463
36. Hanamura I., Iida S., Akano Y., et al. Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn J Cancer Res 92 6 (2001) 638-644
37. Smadja N.V., Leroux D., Soulier J., et al. Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases. Genes Chromosomes Cancer 38 3 (2003) 234-239
38. Fonseca R., Bailey R.J., Ahmann G.J., et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 100 4 (2002) 1417-1424
39. Avet-Loiseau H., Facon T., Daviet A., et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res 59 18 (1999) 4546-4550
40. Kaufmann H., Ackermann J., Baldia C., et al. Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma. Leukemia 18 11 (2004) 1879-1882
41. Hardin J., Waddell M., Page C.D., et al. Evaluation of multiple models to distinguish closely related forms of disease using DNA microarray data: an application to multiple myeloma. Stat Appl Genet Mol Biol 3 (2004) [article10]
42. Zhan F., Hardin J., Kordsmeier B., et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 99 5 (2002) 1745-1757
43. Zhan F., Barlogie B., Arzoumanian V., et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 109 4 (2007) 1692-1700
44. Paquette R.L., Berenson J., Lichtenstein A., et al. Oncogenes in multiple myeloma: point mutation of N-ras. Oncogene 5 11 (1990) 1659-1663
45. Neri A., Murphy J.P., Cro L., et al. Ras oncogene mutation in multiple myeloma. J Exp Med 170 5 (1989) 1715-1725
46. Bezieau S., Devilder M.C., Avet-Loiseau H., et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat 18 3 (2001) 212-224
47. Liu P., Leong T., Quam L., et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 88 7 (1996) 2699-2706
48. Corradini P., Ladetto M., Voena C., et al. Mutational activation of N- and K-ras oncogenes in plasma cell dyscrasias. Blood 81 10 (1993) 2708-2713
49. Rasmussen T., Kuehl M., Lodahl M., et al. Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Blood 105 1 (2005) 317-323
50. Avet-Loiseau H., Facon T., Grosbois B., 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 99 6 (2002) 2185-2191
51. Keats J.J., Reiman T., Maxwell C.A., et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101 4 (2003) 1520-1529
52. Malgeri U., Baldini L., Perfetti V., et al. Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription-polymerase chain reaction analysis of IGH-MMSET fusion transcripts. Cancer Res 60 15 (2000) 4058-4061
53. Agnelli L., Fabris S., Bicciato S., et al. Upregulation of translational machinery and distinct genetic subgroups characterise hyperdiploidy in multiple myeloma. Br J Haematol 136 4 (2007) 565-573
54. Chng W.J., Kumar S., Vanwier S., et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 67 7 (2007) 2982-2989
55. Fassas A.B., Spencer T., Sawyer J., et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol 118 4 (2002) 1041-1047
56. Calasanz M.J., Cigudosa J.C., Odero M.D., et al. Hypodiploidy and 22q11 rearrangements at diagnosis are associated with poor prognosis in patients with multiple myeloma. Br J Haematol 98 2 (1997) 418-425
57. Chng W.J., Santana-Davila R., Van Wier S.A., et al. Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations. Leukemia 20 5 (2006) 807-813
58. Chng W.J., Ketterling R.P., and Fonseca R. Analysis of genetic abnormalities provides insights into genetic evolution of hyperdiploid myeloma. Genes Chromosomes Cancer 45 12 (2006) 1111-1120
59. Potter M., and Wiener F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13 10 (1992) 1681-1697
60. Fonseca R., Blood E.A., Oken M.M., et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 99 10 (2002) 3735-3741
61. Avet-Loiseau H., Li J.Y., Facon T., et al. High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res 58 24 (1998) 5640-5645
62. Keats J.J., Reiman T., Belch A.R., et al. Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma. Leuk Lymphoma 47 11 (2006) 2289-2300
63. Keats J.J., Maxwell C.A., Taylor B.J., et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 105 10 (2005) 4060-4069
64. Santra M., Zhan F., Tian E., et al. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101 6 (2003) 2374-2376
65. Stewart J.P., Thompson A., Santra M., et al. Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. Br J Haematol 126 1 (2004) 72-76
66. Hudlebusch H.R., Theilgaard-Monch K., Lodahl M., et al. Identification of ID-1 as a potential target gene of MMSET in multiple myeloma. Br J Haematol 130 5 (2005) 700-708
67. Plowright E.E., Li Z., Bergsagel P.L., et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 95 3 (2000) 992-998
68. Ronchetti D., Greco A., Compasso S., 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 20 27 (2001) 3553-3562
69. Li Z., Zhu Y.X., Plowright E.E., et al. The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 97 8 (2001) 2413-2419
70. Grand E.K., Chase A.J., Heath C., et al. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia 18 5 (2004) 962-966
71. Trudel S., Ely S., Farooqi Y., et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 103 9 (2004) 3521-3528
72. Trudel S., Li Z.H., Wei E., et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105 7 (2005) 2941-2948
73. Trudel S., Stewart A.K., Rom E., et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 107 10 (2006) 4039-4046
74. Todoerti K., Ronchetti D., Agnelli L., et al. Transcription repression activity is associated with the type I isoform of the MMSET gene involved in t(4;14) in multiple myeloma. Br J Haematol 131 2 (2005) 214-218
75. Rosati R., La Starza R., Veronese A., et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99 10 (2002) 3857-3860
76. Angrand P.O., Apiou F., Stewart A.F., et al. NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74 1 (2001) 79-88
77. Tonon G., Wong K.K., Maulik G., et al. High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A 102 27 (2005) 9625-9630
78. Jaju R.J., Fidler C., Haas O.A., et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 98 4 (2001) 1264-1267
79. Fonseca R., Blood E., Rue M., et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 11 (2003) 4569-4575
80. Avet-Loiseau H., Attal M., Moreau P., et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109 8 (2007) 3489-3495
81. Chang H., Sloan S., Li D., et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 125 1 (2004) 64-68
82. Winkler J.M., Greipp P., and Fonseca R. t(4;14)(p16.3;q32) is strongly associated with a shorter survival in myeloma patients. Br J Haematol 120 1 (2003) 170-171
83. Moreau P., Facon T., Leleu X., et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100 5 (2002) 1579-1583
84. Rasmussen T., Knudsen L.M., Dahl I.M., et al. C-MAF oncogene dysregulation in multiple myeloma: frequency and biological relevance. Leuk Lymphoma 44 10 (2003) 1761-1766
85. Hurt E.M., Wiestner A., Rosenwald A., et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 5 2 (2004) 191-199
86. Lombardi L., Poretti G., Mattioli M., et al. Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosomes Cancer 46 3 (2007) 226-238
87. Suzuki A., Iida S., Kato-Uranishi M., et al. ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene 24 46 (2005) 6936-6944
88. Tian E., Zhan F., Walker R., et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349 26 (2003) 2483-2494
89. Robbiani D.F., Colon K., Ely S., et al. Osteopontin dysregulation and lytic bone lesions in multiple myeloma. Hematol Oncol 25 1 (2007) 16-20
90. Largo C., Saez B., Alvarez S., et al. Multiple myeloma primary cells show a highly rearranged unbalanced genome with amplifications and homozygous deletions irrespective of the presence of immunoglobulin-related chromosome translocations. Haematologica 92 6 (2007) 795-802
91. Largo C., Alvarez S., Saez B., et al. Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma. Haematologica 91 2 (2006) 184-191
92. Walker B.A., Leone P.E., Jenner M.W., et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood 108 5 (2006) 1733-1743
93. Whitfield M.L., George L.K., Grant G.D., et al. Common markers of proliferation. Nat Rev Cancer 6 2 (2006) 99-106
94. Mulligan G., Mitsiades C., Bryant B., et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 109 8 (2007) 3177-3188
95. Avet-Loiseau H., Andree-Ashley L.E., Moore II D., et al. Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukemia measured using comparative genomic hybridization. Genes Chromosomes Cancer 19 2 (1997) 124-133
96. Sawyer J.R., Tricot G., Mattox S., et al. Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood 91 5 (1998) 1732-1741
97. Gutierrez N.C., Garcia J.L., Hernandez J.M., et al. Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood 104 9 (2004) 2661-2666
98. Cremer F.W., Bila J., Buck I., et al. Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chromosomes Cancer 44 2 (2005) 194-203
99. Fonseca R., Van Wier S.A., Chng W.J., et al. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia 20 11 (2006) 2034-2040
100. Chang H., Qi X., Trieu Y., et al. Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation. Br J Haematol 135 4 (2006) 486-491
101. Le Baccon P., Leroux D., Dascalescu C., et al. Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma. Genes Chromosomes Cancer 32 3 (2001) 250-264
102. Sawyer J.R., Tricot G., Lukacs J.L., et al. Genomic instability in multiple myeloma: evidence for jumping segmental duplications of chromosome arm 1q. Genes Chromosomes Cancer 42 1 (2005) 95-106
103. Chang H., Yeung J., Xu W., et al. Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation. Br J Haematol 134 6 (2006) 613-615
104. Wu K.L., Beverloo B., Lokhorst H.M., et al. Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Br J Haematol 136 4 (2007) 615-623
105. Shaughnessy Jr. J.D., Zhan F., Burington B.E., et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109 6 (2007) 2276-2284
106. Zhan F., Colla S., Wu X., et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood 109 11 (2007) 4995-5001
107. Tricot G., Barlogie B., Jagannath S., et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 86 11 (1995) 4250-4256
108. Avet-Louseau H., Daviet A., Sauner S., et al. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 111 4 (2000) 1116-1117
109. Fonseca R., Oken M.M., Harrington D., et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 15 6 (2001) 981-986
110. Shaughnessy J., Tian E., Sawyer J., et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood 96 4 (2000) 1505-1511
111. Facon T., Avet-Loiseau H., Guillerm G., et al. Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97 6 (2001) 1566-1571
112. Zojer N., Konigsberg R., Ackermann J., et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 95 6 (2000) 1925-1930
113. Konigsberg R., Ackermann J., Kaufmann H., et al. Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia 14 11 (2000) 1975-1979
114. Fonseca R., Oken M.M., and Greipp P.R. 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 98 4 (2001) 1271-1272
115. Mertens D., Wolf S., Schroeter P., et al. Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia. Blood 99 11 (2002) 4116-4121
116. Elnenaei M.O., Hamoudi R.A., Swansbury J., et al. Delineation of the minimal region of loss at 13q14 in multiple myeloma. Genes Chromosomes Cancer 36 1 (2003) 99-106
117. Desikan R., Barlogie B., Sawyer J., et al. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95 12 (2000) 4008-4010
118. Fonseca R., Harrington D., Oken M.M., et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study. Cancer Res 62 3 (2002) 715-720
119. Shaughnessy J., Jacobson J., Sawyer J., et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with total therapy I: interpretation in the context of global gene expression. Blood 101 10 (2003) 3849-3856
120. Gutierrez N.C., Castellanos M.V., Martin M.L., et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21 1 (2007) 143-150
121. Wullich B., Riedinger S., Brinck U., et al. Evidence for gains at 15q and 20q in brain metastases of prostate cancer. Cancer Genet Cytogenet 154 2 (2004) 119-123
122. Fujita Y., Sakakura C., Shimomura K., et al. Chromosome arm 20q gains and other genomic alterations in esophageal squamous cell carcinoma, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization. Hepatogastroenterology 50 54 (2003) 1857-1863
123. Panani A.D., Ferti A.D., Papaxoinis C., et al. Cytogenetic data as a prognostic factor in multiple myeloma patients: involvement of 1p12 region an adverse prognostic factor. Anticancer Res 24 6 (2004) 4141-4146
124. Neri A., Baldini L., Trecca D., et al. p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy. Blood 81 1 (1993) 128-135
125. Preudhomme C., Facon T., Zandecki M., et al. Rare occurrence of P53 gene mutations in multiple myeloma. Br J Haematol 81 3 (1992) 440-443
126. Portier M., Moles J.P., Mazars G.R., et al. p53 and RAS gene mutations in multiple myeloma. Oncogene 7 12 (1992) 2539-2543
127. Corradini P., Inghirami G., Astolfi M., et al. Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias. Leukemia 8 5 (1994) 758-767
128. Mazars G.R., Portier M., Zhang X.G., et al. Mutations of the p53 gene in human myeloma cell lines. Oncogene 7 5 (1992) 1015-1018
129. Chng W.J., Price-Troska T., Gonzalez-Paz N., et al. Clinical significance of TP53 mutation in myeloma. Leukemia 21 3 (2007) 582-584
130. Avet-Loiseau H., Li J.Y., Godon C., et al. P53 deletion is not a frequent event in multiple myeloma. Br J Haematol 106 3 (1999) 717-719
131. Chang H., Qi C., Yi Q.L., et al. p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 105 1 (2005) 358-360
132. Gertz M.A., Lacy M.Q., Dispenzieri A., 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 106 8 (2005) 2837-2840
133. Skopelitou A., Hadjiyannakis M., Tsenga A., et al. Expression of C-myc p62 oncoprotein in multiple myeloma: an immunohistochemical study of 180 cases. Anticancer Res 13 4 (1993) 1091-1095
134. Palumbo A.P., Pileri A., Dianzani U., et al. Altered expression of growth-regulated protooncogenes in human malignant plasma cells. Cancer Res 49 17 (1989) 4701-4704
135. Selvanayagam P., Blick M., Narni F., et al. Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma. Blood 71 1 (1988) 30-35
136. Pope B., Brown R., Luo X.F., et al. Disease progression in patients with multiple myeloma is associated with a concurrent alteration in the expression of both oncogenes and tumour suppressor genes and can be monitored by the oncoprotein phenotype. Leuk Lymphoma 25 5-6 (1997) 545-554
137. Fabris S., Storlazzi C.T., Baldini L., et al. Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma. Genes Chromosomes Cancer 37 3 (2003) 261-269
138. Shou Y., Martelli M.L., Gabrea A., et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A 97 1 (2000) 228-233
139. Hollis G.F., Gazdar A.F., Bertness V., et al. Complex translocation disrupts c-myc regulation in a human plasma cell myeloma. Mol Cell Biol 8 1 (1988) 124-129
140. Avet-Loiseau H., Gerson F., Magrangeas F., et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 98 10 (2001) 3082-3086
141. Elnenaei M.O., Gruszka-Westwood A.M., A'Hernt R., et al. Gene abnormalities in multiple myeloma; the relevance of TP53, MDM2, and CDKN2A. Haematologica 88 5 (2003) 529-537
142. Ng M.H., Chung Y.F., Lo K.W., et al. Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 89 7 (1997) 2500-2506
143. Gonzalez-Paz N., Chng W.J., McClure R.F., et al. Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications. Blood 109 3 (2007) 1228-1232
144. Dib A., Barlogie B., Shaughnessy Jr. J.D., et al. Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma. Blood 109 3 (2007) 1337-1338
145. Ribas C., Colleoni G.W., Felix R.S., et al. p16 gene methylation lacks correlation with angiogenesis and prognosis in multiple myeloma. Cancer Lett 222 2 (2005) 247-254
146. Kramer A., Schultheis B., Bergmann J., et al. Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma. Leukemia 16 9 (2002) 1844-1851
147. Sarasquete M.E., Garcia-Sanz R., Armellini A., et al. The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma. Haematologica 91 11 (2006) 1551-1554
148. Mateos M.V., Garcia-Sanz R., Lopez-Perez R., et al. Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival. Br J Haematol 118 4 (2002) 1034-1040
149. Dib A., Peterson T.R., Raducha-Grace L., et al. Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression. Cell Div 1 (2006) 23
150. Tasaka T., Berenson J., Vescio R., et al. Analysis of the p16INK4A, p15INK4B and p18INK4C genes in multiple myeloma. Br J Haematol 96 1 (1997) 98-102
151. Matsui W., Huff C.A., Wang Q., et al. Characterization of clonogenic multiple myeloma cells. Blood 103 6 (2004) 2332-2336
152. Peacock C.D., Wang Q., Gesell G.S., et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 104 10 (2007) 4048-4053
153. Huntly B.J., and Gilliland D.G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5 4 (2005) 311-321