Blood Reviews
Volume 23, Issue 5 , Pages 205-216 , September 2009

Molecular biology of mantle cell lymphoma: From profiling studies to new therapeutic strategies

  • Antònia Obrador-Hevia

      Affiliations

    • Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain
  • ,
  • Silvia Fernández de Mattos

      Affiliations

    • Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain
    • Corresponding Author InformationCorresponding authors. Address: Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain. Tel.: +34 91 5868000; fax: +34 91 5868018 (J. Rodríguez), tel.: +34 971 173004; fax: +34 971 259501 (S. Fernández de Mattos).
  • ,
  • Priam Villalonga

      Affiliations

    • Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain
  • ,
  • José Rodríguez

      Affiliations

    • Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain
    • Hospital Universitario Gregorio Marañón, Oncology Department, Dr Esquerdo, 46. E-28007 Madrid, Spain
    • Corresponding Author InformationCorresponding authors. Address: Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain. Tel.: +34 91 5868000; fax: +34 91 5868018 (J. Rodríguez), tel.: +34 971 173004; fax: +34 971 259501 (S. Fernández de Mattos).

References 

  1. Andersen NS, Jensen MK, De Nully Brown P, Geisler CH. A Danish population-based analysis of 105 mantle cell lymphoma patients: incidences, clinical features, response, survival and prognostic factors. Eur J Cancer. 2002;38(3):401–408
  2. Bosch F, Lopez-Guillermo A, Campo E, Ribera JM, Conde E, Piris MA, et al. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer. 1998;82(3):567–575
  3. Jaffe ES, Harris NL, Diebold J, Muller-Hermelink HK. World Health Organization Classification of lymphomas: a work in progress. Ann Oncol. 1998;9(Suppl. 5):S25–S30
  4. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol. 2000;13(2):193–207
  5. Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol. 1992;16(7):637–640
  6. Salar A, Juanpere N, Bellosillo B, Domingo-Domenech E, Espinet B, Seoane A, et al. Gastrointestinal involvement in mantle cell lymphoma: a prospective clinic, endoscopic, and pathologic study. Am J Surg Pathol. 2006;30(10):1274–1280
  7. Akiyama N, Tsuruta H, Sasaki H, Sakamoto H, Hamaguchi M, Ohmura Y, 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. 1994;54(2):377–379
  8. Jaffe ES, Harris NL, Diebold J, Muller-Hermelink HK. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues A progress report. Am J Clin Pathol. 1999;111(Suppl. 1):S8–12
  9. Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Rosenwald A, et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood. 2005;106(13):4315–4321
  10. Rosenwald A, Staudt LM. Gene expression profiling of diffuse large B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl. 3):S41–47
  11. Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood. 2000;95(7):2253–2261
  12. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. Embo J. 1994;13(9):2124–2130
  13. Lovec H, Grzeschiczek A, Kowalski MB, Moroy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. Embo J. 1994;13(15):3487–3495
  14. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985;318(6046):533–538
  15. Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA. Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene. 2006;25(7):998–1007
  16. Langdon WY, Harris AW, Cory S. Acceleration of B-lymphoid tumorigenesis in E mu-myc transgenic mice by v-H-ras and v-raf but not v-abl. Oncogene Res. 1989;4(4):253–258
  17. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57(1):79–88
  18. Rosenbaum H, Webb E, Adams JM, Cory S, Harris AW. N-myc transgene promotes B lymphoid proliferation, elicits lymphomas and reveals cross-regulation with c-myc. Embo J. 1989;8(3):749–755
  19. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–442
  20. Bryant J, Pham L, Yoshimura L, Tamayo A, Ordonez N, Ford RJ. Development of intermediate-grade (mantle cell) and low-grade (small lymphocytic and marginal zone) human non-Hodgkin’s lymphomas xenotransplanted in severe combined immunodeficiency mouse models. Lab Invest. 2000;80(4):557–573
  21. M’Kacher R, Farace F, Bennaceur-Griscelli A, Violot D, Clausse B, Dossou J, et al. Blastoid mantle cell lymphoma: evidence for nonrandom cytogenetic abnormalities additional to t(11;14) and generation of a mouse model. Cancer Genet Cytogenet. 2003;143(1):32–38
  22. Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, et al. A severe combined immunodeficient-hu in vivo mouse model of human primary mantle cell lymphoma. Clin Cancer Res. 2008;14(7):2154–2160
  23. Smith MR, Joshi I, Jin F, Al-Saleem T. Murine model for mantle cell lymphoma. Leukemia. 2006;20(5):891–893
  24. Ford RJ, Shen L, Lin-Lee YC, Pham LV, Multani A, Zhou HJ, et al. Development of a murine model for blastoid variant mantle-cell lymphoma. Blood. 2007;109(11):4899–4906
  25. Allen JE, Hough RE, Goepel JR, Bottomley S, Wilson GA, Alcock HE, et al. Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization. Br J Haematol. 2002;116(2):291–298
  26. Bea S, Ribas M, Hernandez JM, Bosch F, Pinyol M, Hernandez L, et al. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Blood. 1999;93(12):4365–4374
  27. Bentz M, Plesch A, Bullinger L, Stilgenbauer S, Ott G, Muller-Hermelink HK, et al. T(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia. Gene Chromosome Cancer. 2000;27(3):285–294
  28. Jarosova M, Papajik T, Holzerova M, Dusek L, Pikalova Z, Lakoma I, et al. High incidence of unbalanced chromosomal changes in mantle cell lymphoma detected by comparative genomic hybridization. Leuk Lymphoma. 2004;45(9):1835–1846
  29. Kohlhammer H, Schwaenen C, Wessendorf S, Holzmann K, Kestler HA, Kienle D, et al. Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions. Blood. 2004;104(3):795–801
  30. Monni O, Oinonen R, Elonen E, Franssila K, Teerenhovi L, Joensuu H, et al. Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma. Genes Chromosomes Cancer. 1998;21(4):298–307
  31. Salaverria I, Zettl A, Bea S, Moreno V, Valls J, Hartmann E, et al. Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature. J Clin Oncol. 2007;25(10):1216–1222
  32. Thelander EF, Walsh SH, Thorselius M, Laurell A, Landgren O, Larsson C, et al. Mantle cell lymphomas with clonal immunoglobulin V(H)3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V(H) genes. Mod Pathol. 2005;18(3):331–339
  33. de Leeuw RJ, Davies JJ, Rosenwald A, Bebb G, Gascoyne RD, Dyer MJ, et al. Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes. Hum Mol Genet. 2004;13(17):1827–1837
  34. Flordal Thelander E, Ichimura K, Collins VP, Walsh SH, Barbany G, Hagberg A, et al. Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma. Leuk Res. 2007;31(9):1219–1230
  35. Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V, et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood. 2007;109(1):271–280
  36. Rubio-Moscardo F, Climent J, Siebert R, Piris MA, Martin-Subero JI, Nielander I, et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood. 2005;105(11):4445–4454
  37. Schraders M, Pfundt R, Straatman HM, Janssen IM, van Kessel AG, Schoenmakers EF, et al. Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide array-based comparative genomic hybridization. Blood. 2005;105(4):1686–1693
  38. Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24(8):1348–1358
  39. Vater I, Wagner F, Kreuz M, Berger H, Martin-Subero JI, Pott C, et al. GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma. Br J Haematol 2008.
  40. Bea S, Salaverria I, Armengol L, Pinyol M, Fernandez V, Hartmann EM, et al. Uniparental disomies, homozygous deletions, amplifications and target genes in mantle cell lymphoma revealed by integrative high-resolution whole genome profiling. Blood 2008.
  41. Nielaender I, Martin-Subero JI, Wagner F, Martinez-Climent JA, Siebert R. Partial uniparental disomy: a recurrent genetic mechanism alternative to chromosomal deletion in malignant lymphoma. Leukemia. 2006;20(5):904–905
  42. Blenk S, Engelmann JC, Pinkert S, Weniger M, Schultz J, Rosenwald A, et al. Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis. BMC Cancer. 2008;8(1):106
  43. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–511
  44. Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185–197
  45. Ek S, Hogerkorp CM, Dictor M, Ehinger M, Borrebaeck CA. Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. Cancer Res. 2002;62(15):4398–4405
  46. Hofmann WK, de Vos S, Tsukasaki K, Wachsman W, Pinkus GS, Said JW, et al. Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood. 2001;98(3):787–794
  47. Martinez N, Camacho FI, Algara P, Rodriguez A, Dopazo A, Ruiz-Ballesteros E, et al. The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res. 2003;63(23):8226–8232
  48. Rinaldi A, Kwee I, Taborelli M, Largo C, Uccella S, Martin V, et al. Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br J Haematol. 2006;132(3):303–316
  49. Korz C, Pscherer A, Benner A, Mertens D, Schaffner C, Leupolt E, et al. Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Blood. 2002;99(12):4554–4561
  50. Nagy B, Lundan T, Larramendy ML, Aalto Y, Zhu Y, Niini T, et al. Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol. 2003;120(3):434–441
  51. Xerri L, Devilard E, Bouabdallah R, Hassoun J, Chaperot L, Birg F, et al. Quantitative analysis detects ubiquitous expression of apoptotic regulators in B cell non-Hodgkin’s lymphomas. Leukemia. 1999;13(10):1548–1553
  52. Tracey L, Perez-Rosado A, Artiga MJ, Camacho FI, Rodriguez A, Martinez N, et al. Expression of the NF-kappaB targets BCL2 and BIRC5/Survivin characterizes small B-cell and aggressive B-cell lymphomas, respectively. J Pathol. 2005;206(2):123–134
  53. Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J, Livingston DM. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993;73(3):487–497
  54. Dreyling MH, Bullinger L, Ott G, Stilgenbauer S, Muller-Hermelink HK, Bentz M, et al. Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res. 1997;57(20):4608–4614
  55. Gronbaek K, Nedergaard T, Andersen MK, thor Straten P, Guldberg P, Moller P, et al. Concurrent disruption of cell cycle associated genes in mantle cell lymphoma: a genotypic and phenotypic study of cyclin D1, p16, p15, p53 and pRb. Leukemia. 1998;12(8):1266–1271
  56. Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, et al. P16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin’s lymphomas. Blood. 1998;91(8):2977–2984
  57. Pinyol M, Hernandez L, Cazorla M, Balbin M, Jares P, Fernandez PL, et al. Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. Blood. 1997;89(1):272–280
  58. Bea S, Tort F, Pinyol M, Puig X, Hernandez L, Hernandez S, et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res. 2001;61(6):2409–2412
  59. Hernandez L, Bea S, Pinyol M, Ott G, Katzenberger T, Rosenwald A, et al. CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus. Cancer Res. 2005;65(6):2199–2206
  60. Pinyol M, Bea S, Pla L, Ribrag V, Bosq J, Rosenwald A, et al. Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis. Blood. 2007;109(12):5422–5429
  61. Camacho E, Hernandez L, Hernandez S, Tort F, Bellosillo B, Bea S, et al. ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood. 2002;99(1):238–244
  62. Fernandez V, Hartmann E, Ott G, Campo E, Rosenwald A. Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol. 2005;23(26):6364–6369
  63. Rummel MJ, de Vos S, Hoelzer D, Koeffler HP, Hofmann WK. Altered apoptosis pathways in mantle cell lymphoma. Leuk Lymphoma. 2004;45(1):49–54
  64. Ghobrial IM, McCormick DJ, Kaufmann SH, Leontovich AA, Loegering DA, Dai NT, et al. Proteomic analysis of mantle-cell lymphoma by protein microarray. Blood. 2005;105(9):3722–3730
  65. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003;171(1):88–95
  66. Rudelius M, Pittaluga S, Nishizuka S, Pham TH, Fend F, Jaffe ES, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood. 2006;108(5):1668–1676
  67. Rizzatti EG, Falcao RP, Panepucci RA, Proto-Siqueira R, Anselmo-Lima WT, Okamoto OK, et al. Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways. Br J Haematol. 2005;130(4):516–526
  68. Dreyling M, Unterhalt M, Weigert O, Hiddemann W. Therapy of mantle cell lymphoma. Internist (Berl). 2007;48(4):382–388
  69. Fisher RI. Mantle cell lymphoma: at last, some hope for successful innovative treatment strategies. J Clin Oncol. 2005;23(4):657–658
  70. Ghielmini M, Schmitz SF, Burki K, Pichert G, Betticher DC, Stupp R, et al. The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 2000;11(Suppl. 1):123–126
  71. Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105(7):2677–2684
  72. Andersen NS, Pedersen L, Elonen E, Johnson A, Kolstad A, Franssila K, et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant. Eur J Haematol. 2003;71(2):73–80
  73. Khouri I, Saliba RM, Okoroji GJ, Acholonu S, Champlin R. Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first remission: the prognostic value of B2m and the tumor score. Cancer. 2003;98:2630–2635
  74. Maris MB, Sandmaier BM, Storer BE, Chauncey T, Stuart MJ, Maziarz RT, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. 2004;104(12):3535–3542
  75. Khouri IF, Lee MS, Saliba RM, Jun G, Fayad L, Younes A, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21(23):4407–4412
  76. Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005;11(9):986–991
  77. Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?. J Cell Sci. 2001;114(Pt 16):2903–2910
  78. Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 2001;98(20):10983–10985
  79. Dal Col J, Zancai P, Terrin L, Guidoboni M, Ponzoni M, Pavan A, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood. 2008;111(10):5142–5151
  80. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA. 1994;91(26):12574–12578
  81. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98(18):10314–10319
  82. Kawamata S, Sakaida H, Hori T, Maeda M, Uchiyama T. The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood. 1998;91(2):561–569
  83. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem. 1998;273(23):14424–14429
  84. Peponi E, Drakos E, Reyes G, Leventaki V, Rassidakis GZ, Medeiros LJ. Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol. 2006;169(6):2171–2180
  85. Hipp S, Ringshausen I, Oelsner M, Bogner C, Peschel C, Decker T. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica. 2005;90(10):1433–1434
  86. Yazbeck VY, Buglio D, Georgakis GV, Li Y, Iwado E, Romaguera JE, et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol. 2008;36(4):443–450
  87. Haritunians T, Mori A, O’Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia. 2007;21(2):333–339
  88. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005;23(23):5347–5356
  89. Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12(17):5165–5173
  90. Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2008;14(9):2756–2762
  91. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87(1):13–20
  92. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–310
  93. Bottero V, Withoff S, Verma IM. NF-kappaB and the regulation of hematopoiesis. Cell Death Differ. 2006;13(5):785–797
  94. Roue G, Perez-Galan P, Lopez-Guerra M, Villamor N, Campo E, Colomer D. Selective inhibition of IkappaB kinase sensitizes mantle cell lymphoma B cells to TRAIL by decreasing cellular FLIP level. J Immunol. 2007;178(3):1923–1930
  95. O’Connor OA. Targeting histones and proteasomes: new strategies for the treatment of lymphoma. J Clin Oncol. 2005;23(26):6429–6436
  96. Chiarle R, Budel LM, Skolnik J, Frizzera G, Chilosi M, Corato A, et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood. 2000;95(2):619–626
  97. Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006;107(1):257–264
  98. Weigert O, Pastore A, Rieken M, Lang N, Hiddemann W, Dreyling M. Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. Leukemia. 2007;21(3):524–528
  99. O’Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2005;23(4):676–684
  100. Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(4):667–675
  101. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24(30):4867–4874
  102. Belch A, Kouroukis CT, Crump M, Sehn L, Gascoyne RD, Klasa R, et al. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol. 2007;18(1):116–121
  103. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109(10):4441–4449
  104. Wang M, Han XH, Zhang L, Yang J, Qian JF, Shi YK, et al. Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia. 2008;22(1):179–185
  105. Jones LK, Saha V. Chromatin modification, leukaemia and implications for therapy. Br J Haematol. 2002;118(3):714–727
  106. Heider U, Kaiser M, Sterz J, Zavrski I, Jakob C, Fleissner C, et al. Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma. Eur J Haematol. 2006;76(1):42–50
  107. Sakajiri S, Kumagai T, Kawamata N, Saitoh T, Said JW, Koeffler HP. Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines. Exp Hematol. 2005;33(1):53–61
  108. Kawamata N, Chen J, Koeffler HP. Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood. 2007;110(7):2667–2673
  109. O’Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol. 2006;24(1):166–173
  110. Heider U, von Metzler I, Kaiser M, Rosche M, Sterz J, Rotzer S, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol. 2008;80(2):133–142
  111. Morimoto RI, Santoro MG. Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection. Nat Biotechnol. 1998;16(9):833–838
  112. Georgakis GV, Li Y, Younes A. The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9. Br J Haematol. 2006;135(1):68–71
  113. Sherr CJ. Mammalian G1 cyclins. Cell. 1993;73(6):1059–1065
  114. Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–555
  115. Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst. 2000;92(5):376–387
  116. Kouroukis CT, Belch A, Crump M, Eisenhauer E, Gascoyne RD, Meyer R, et al. Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003;21(9):1740–1745
  117. Lacrima K, Valentini A, Lambertini C, Taborelli M, Rinaldi A, Zucca E, et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol. 2005;16(7):1169–1176
  118. Park IW, Reddy MV, Reddy EP, Groopman JE. Evaluation of novel cell cycle inhibitors in mantle cell lymphoma. Oncogene. 2007;26(38):5635–5642
  119. Ramanarayanan J, Hernandez-Ilizaliturri FJ, Chanan-Khan A, Czuczman MS. Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab. Br J Haematol. 2004;127(5):519–530
  120. O’Brien SM, Cunningham CC, Golenkov AK, Turkina AG, Novick SC, Rai KR. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23(30):7697–7702
  121. Tucker CA, Kapanen AI, Chikh G, Hoffman BG, Kyle AH, Wilson IM, et al. Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-kappaB, p53, bax, and p27 levels. Mol Cancer Ther. 2008;7(4):749–758
  122. Paoluzzi L, Gonen M, Gardner JR, Mastrella J, Yang D, Holmlund J, et al. Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood. 2008;111(11):5350–5358
  123. Paoluzzi L, Gonen M, Bhagat G, Furman RR, Gardner JR, Scotto L, et al. The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood. 2008;112(7):2906–2916
  124. Henson ES, Johnston JB, Gibson SB. The role of TRAIL death receptors in the treatment of hematological malignancies. Leuk Lymphoma. 2008;49(1):27–35
  125. Eucker J, Sterz J, Krebbel H, Zavrski I, Kaiser M, Zang C, et al. Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma. Anticancer Drugs. 2006;17(7):763–769
  126. Damaj G, Lefrere F, Delarue R, Varet B, Furman R, Hermine O. Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia. 2003;17(9):1914–1915
  127. Kaufmann H, Raderer M, Wohrer S, Puspok A, Bankier A, Zielinski C, et al. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood. 2004;104(8):2269–2271
  128. Langenfeld J, Kiyokawa H, Sekula D, Boyle J, Dmitrovsky E. Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci USA. 1997;94(22):12070–12074
  129. Guidoboni M, Zancai P, Cariati R, Rizzo S, Dal Col J, Pavan A, et al. Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. Cancer Res. 2005;65(2):587–595
  130. Haluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer. 2002;38(13):1685–1700
  131. David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood. 2005;106(13):4322–4329
  132. Rolland D, Camara-Clayette V, Barbarat A, Salles G, Coiffier B, Ribrag V, et al. Farnesyltransferase inhibitor R115777 inhibits cell growth and induces apoptosis in mantle cell lymphoma. Cancer Chemother Pharmacol. 2008;61(5):855–863
  133. Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA, et al. PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol. 2002;3(8):780–786
  134. Decouvelaere AV, Morschhauser F, Buob D, Copin MC, Dumontet C. Heterogeneity of protein kinase C beta(2) expression in lymphoid malignancies. Histopathology. 2007;50(5):561–566
  135. Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN, et al. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res. 2005;65(16):7462–7469
  136. Morschhauser F, Seymour JF, Kluin-Nelemans HC, Grigg A, Wolf M, Pfreundschuh M, et al. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann Oncol. 2008;19(2):247–253
  137. Lepelletier Y, Camara-Clayette V, Jin H, Hermant A, Coulon S, Dussiot M, et al. Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments. Cancer Res. 2007;67(3):1145–1154
  138. Ek S, Ortega E, Borrebaeck CA. Transcriptional profiling and assessment of cell lines as in vitro models for mantle cell lymphoma. Leuk Res. 2005;29(2):205–213
  139. Ek S, Andreasson U, Hober S, Kampf C, Ponten F, Uhlen M, et al. From gene expression analysis to tissue microarrays: a rational approach to identify therapeutic and diagnostic targets in lymphoid malignancies. Mol Cell Proteomics. 2006;5(6):1072–1081
  140. Ortega-Paino E, Fransson J, Ek S, Borrebaeck CA. Functionally associated targets in mantle cell lymphoma as defined by DNA microarrays and RNA interference. Blood. 2008;111(3):1617–1624
  141. Ek S, Bjorck E, Hogerkorp CM, Nordenskjold M, Porwit-MacDonald A, Borrebaeck CA. Mantle cell lymphomas acquire increased expression of CCL4, CCL5 and 4–1BB-L implicated in cell survival. Int J Cancer. 2006;118(8):2092–2097

PII: S0268-960X(09)00020-4

doi: 10.1016/j.blre.2009.03.001

Blood Reviews
Volume 23, Issue 5 , Pages 205-216 , September 2009