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Spotlight on Chronic Lymphocytic Leukemia

Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia

Leukemia volume 16, pages 1028–1034 (2002)Cite this article

Abstract

To investigate the role of the cell cycle regulators p21Waf1, p27Kip1, retinoblastoma (Rb), and cyclin D1 in Richter's transformation of chronic lymphocytic leukemia (CLL), we analyzed 19 CLL and eight Richter's syndrome (RS) tumors, previously characterized for p53 and ARF/INK4a abnormalities. p21Waf1immunohistochemical expression was negative in 12 of 15 CLL (80%), whereas it was moderate or strong in three of seven RS (43%). p21Waf1 gene was in germline configuration in all the tumors analyzed. Four immunohistochemical patterns of p53 and p21Waf1 expression were observed: (1) p53−/p21− in 10 of 15 CLL (67%), but only in two of six RS (33%); (2) p53+/p21+ in three CLL (20%) and two RS (33%); (3) p53−/p21+ in one RS; and (4) p53++/p21− in two CLL and one RS. Two p53+/p21+ CLL evolved into RS. p53 mutations clustered around the p53++/p21− (two CLL and one RS) and p53−/p21− (one CLL and one RS) tumors. While the majority of CLL displayed strong p27 immunoreactivity, RS tumors were constantly p27-negative. p27Kip1 gene was in germline configuration in all the tumors analyzed. Most CLL cases were negative for Rb expression. In contrast, all RS exhibited strong Rb expression. Cyclin D1 overexpression was only detected in one CLL evolving into RS and one RS. In conclusion, a p53+/p21− immunohistochemical pattern is shown exclusively by p53-mutated CLL/RS. Additionally, our results suggest a possible implication of moderate/strong p21Waf1 expression, loss of p27 expression, and cyclin D1 overexpression in the Richter's transformation of CLL.

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References

  1. Robertson LE, Pugh W, O'Brien S, Kantarjian H, Hirsch-Ginsberg C, Cork A, Mclaughlin P, Cabanillas, Keating MJ . Richter's syndrome: a report on 39 patients J Clin Oncol 1993 11: 1985–1989

    Article  CAS  PubMed  Google Scholar 

  2. Daniel PT . Dissecting the pathways to death Leukemia 2000 14: 2035–2044

    Article  CAS  PubMed  Google Scholar 

  3. Imamura J, Miyoshi I, Koeffler HP . p53 in hematologic malignancies Blood 1994 84: 2412–2421

    CAS  PubMed  Google Scholar 

  4. Hirama T, Koeffler HP . Role of the cyclin-dependent kinase inhibitors in the development of cancer Blood 1995 86: 841–854

    CAS  PubMed  Google Scholar 

  5. Gronbaek K, de Nully Brown P, Moller MB, Nedergaard T, Ralfkiaer E, Moller P, Zeuthen J, Guldberg P . Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma Leukemia 2000 14: 1727–1735

    Article  CAS  PubMed  Google Scholar 

  6. Hernandez L, Fest T, Cazorla M, Teruya-Feldstein J, Bosch F, Peinado MA, Piris MA, Montserrat E, Cardesa A, Jaffe ES, Campo E, Raffeld M . p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas Blood 1996 87: 3351–3359

    CAS  PubMed  Google Scholar 

  7. Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RSK, Dalla-Favera R . p53 mutations are associated with histologic transformation of follicular lymphoma Blood 1993 82: 2289–2295

    CAS  PubMed  Google Scholar 

  8. Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, Montserrat E, Cardesa A, Campo E . P16INK4a gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas Blood 1998 91: 2977–2984

    CAS  PubMed  Google Scholar 

  9. Villuendas R, Sánchez-Beato M, Martínez JC, Saez AI, Martínez-Delgado B, García JF, Mateo MS, Sánchez-Verde L, Benítez J, Martínez P, Piris MA . Loss of p16/INK4a protein expression in non-Hodgkin's lymphomas is a frequent finding associated with tumor progression Am J Pathol 1998 153: 887–897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elenitoba-Johnson KSJ, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M . Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma Blood 1998 91: 4677–4685

    CAS  PubMed  Google Scholar 

  11. Fenaux P, Preudhomme C, Lai JL, Quiquandon I, Jonveaux P, Vanrumbeke M, Sartiaux C, Morel P, Loucheux-Lefebvre MH, Bauters F, Berger R, Kerckhaert JP . Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis Leukemia 1992 6: 246–250

    CAS  PubMed  Google Scholar 

  12. El Rouby S, Thomas A, Costin D, Rosenber CR, Potmesil M, Silber R, Newcomb EW . P53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR-1/MDR-3 gene expression Blood 1993 82: 3452–3459

    CAS  PubMed  Google Scholar 

  13. Lepelley P, Preudhomme C, Vanrumbeke M, Quesnel B, Cosson A, Fenaux P . Detection of p53 mutations in hematological malignancies: comparison between immunocytochemistry and DNA analysis Leukemia 1994 8: 1342–1349

    CAS  PubMed  Google Scholar 

  14. Callet-Bauchu E, Salles G, Gazzo S, Poncet C, Morel D, Pages J, Coiffier B, Coeur P, Felman P . Translocations involving the short arm of chromosome 17 in chronic B-lymphoid disorders: frequent occurrence of dicentric rearrangements and possible association with adverse outcome Leukemia 1999 13: 460–468

    Article  CAS  PubMed  Google Scholar 

  15. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S, Volkmann M, Galle PR, Poutska A, Hunstein W, Lichter P . P53 gene deletions predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias Blood 1995 85: 1580–1589

    PubMed  Google Scholar 

  16. Cordone I, Masi S, Mauro FR, Soddu S, Morsilli O, Valentini T, Vegna ML, Guglielmi C, Mancini F, Giuliacci S, Sacchi A, Mandelli F, Foa R . P53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis Blood 1998 91: 4342–4349

    CAS  PubMed  Google Scholar 

  17. Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, Magrath IT, Knowles DM, Dalla-Favera R . P53 mutations in human lymphoid malignancies: association with Burkitt's lymphoma and chronic lymphocytic leukemia Proc Natl Acad Sci USA 1991 88: 5413–5417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Matolcsy A, Inghirami G, Knowles DM . Molecular genetic demonstration of the diverse evolution of Richter's syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma) Blood 1994 83: 1363–1372

    CAS  PubMed  Google Scholar 

  19. Pinyol M, Hernández L, Martínez A, Cobo F, Hernández S, Beá S, López-Guillermo A, Nayach I, Palacín A, Nadal A, Fernández PL, Montserrat E, Cardesa A, Campo E . INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene Am J Pathol 2000 156: 1987–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer E, Kinzler KW, Vogelstein B . WAF1, a potential mediator of p53 tumor suppression Cell 1993 75: 817–825

    Article  CAS  PubMed  Google Scholar 

  21. Shiohara M, El-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Chen D-L, Vogelstein B, Koeffler HP . Absence of WAF1 mutations in a variety of human malignancies Blood 1994 84: 3781–3784

    CAS  PubMed  Google Scholar 

  22. Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J . Cloning of p27Kip-1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals Cell 1994 78: 59–66

    Article  CAS  PubMed  Google Scholar 

  23. Kawamata N, Morosetti R, Miller CW, Park D, Spirin KS, Nakamaki T, Takeuchi S, Hatta Y, Simpson J, Wilczynski S, Lee YY, Bartram CR, Koeffler HP . Molecular analysis of the cyclin-dependent kinase inhibitor p27/KIP-1 in human malignancies Cancer Res 1995 55: 2266–2269

    CAS  PubMed  Google Scholar 

  24. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M . Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas Nat Med 1997 3: 231–234

    Article  CAS  PubMed  Google Scholar 

  25. Morosetti R, Kawamata N, Gombart AF, Miller CW, Hatta Y, Hirama T, Said JW, Tomonaga M, Koeffler HP . Alterations of the p27Kip1 gene in non-Hodgkin's lymphomas and adult T-cell leukemia/lymphoma Blood 1995 86: 1924–1930

    CAS  PubMed  Google Scholar 

  26. Goodrich DW, Wang NP, Qian Y-W, Lee EY-H, Lee W-H . The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle Cell 1991 67: 293–302

    Article  CAS  PubMed  Google Scholar 

  27. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR . The E2F transcription factor is a cellular target for the Rb protein Cell 1991 65: 1053–1061

    Article  CAS  PubMed  Google Scholar 

  28. Martínez JC, Piris MA, Sánchez-Beato M, Villuendas R, Orradre JL, Algara P, Sánchez-Verde L, Martínez P . Retinoblastoma gene product expression in lymphomas. Correlation with Ki67 growth fraction J Pathol 1993 169: 405–412

    Article  PubMed  Google Scholar 

  29. Weide R, Tiemann M, Pfluger KH, Koppler H, Parvizl B, Wacker HH, Kreipe HH, Havemann K, Parwaresch MR . Altered expression of the retinoblastoma gene product in human high grade non-Hodgkin's lymphomas Leukemia 1994 8: 97–101

    CAS  PubMed  Google Scholar 

  30. Cuneo A, Bigoni R, Negrini M, Bullrich F, Veronese ML, Roberti MG, Bardi A, Rigolin GM, Cavazzini P, Croce CM, Castoldi G . Cytogenetic and interphase cytogenetic characterization of atypical chronic lymphocytic leukemia carrying BCL1 translocation Cancer Res 1997 57: 1144–1150

    CAS  PubMed  Google Scholar 

  31. Cuneo A, Balboni M, Piva N, Rigolin GM, Roberti MG, Mejak C, Moretti S, Bigoni R, Balsamo R, Cavazzini P, Castoldi G . Atypical chronic lymphocytic leukaemia with t(11;14)(q13;q32): karyotype evolution and prolymphocytic transformation Br J Haematol 1995 90: 409–416

    Article  CAS  PubMed  Google Scholar 

  32. Pinyol M, Hernandez L, Cazorla M, Balbin M, Jares P, Fernandez PL, Montserrat E, Cardesa A, Lopez-Otin C, Campo E . Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas Blood 1997 89: 272–280

    CAS  PubMed  Google Scholar 

  33. Chilosi M, Doglioni C, Magalini A, Inghirami G, Krampera M, Nadali G, Rahal D, Pedron S, Benedetti A, Scardoni M, Macri E, Lestani M, Menestrina F, Pizzolo G, Scarpa A . P21/Waf1 cyclin-kinase inhibitor expression in non-hodgkin's lymphomas: a potential marker of p53 tumor-suppressor gene function Blood 1996 88: 4012–4020

    CAS  PubMed  Google Scholar 

  34. Bosch F, Jares P, Campo E, Lopez-Guillermo A, Piris MA, Villamor N, Tassies D, Jaffe ES, Montserrat E, Rozman C, Cardesa A . Prad-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma Blood 1994 84: 2726–2732

    CAS  PubMed  Google Scholar 

  35. Pinyol M, Campo E, Nadal A, Terol MJ, Jares P, Nayach I, Fernández PL, Piris MA, Montserrat E, Cardesa A . Detection of the bcl-1 rearrangement at the major translocation cluster in frozen and paraffin-embedded tissues of mantle cell lymphomas by polymerase chain reaction Am J Clin Pathol 1996 105: 532–537

    Article  CAS  PubMed  Google Scholar 

  36. Mansukhani MM, Osborne BM, Zhong J, Matsushima AY . The pattern of p53 and p21Waf1/CIP1 immunoreactivity in non-Hodgkin's lymphomas predicts p53 gene status Diagn Mol Pathol 1997 6: 222–228

    Article  CAS  PubMed  Google Scholar 

  37. Villuendas R, Pezzella F, Gatter K, Algara P, Sánchez-Beato M, Martínez P, Martínez JC, Muñoz K, García P, Sánchez L, Kocialkowsky S, Campo E, Orradre JL, Piris MA . P21Waf1/CIP1 and MDM2 expression in non-Hodgkin's lymphoma and their relationship to p53 status: a p53+, MDM2−, p21− immunophenotype associated with missense p53 mutations J Pathol 1997 181: 51–61

    Article  CAS  PubMed  Google Scholar 

  38. Maestro R, Gloghini A, Doglioni C, Piccinin S, Vukosavljevic T, Gasparotto D, Carbone A, Boiocchi M . Human non-Hodgkin's lymphomas overexpress a wyld-type form of p53 which is a functional transcriptional activator of the cyclin-dependent kinase inhibitor p21 Blood 1997 89: 2523–2528

    CAS  PubMed  Google Scholar 

  39. Stefanaki K, Tzardi M, Kouvidou CH, Chanotis V, Bolioti M, Vlychou M, Zois M, Kakolyris S, Delides G, Rontogianni D, Geogoulias V, Kanavaros P . Expression of p53, p21, mdm2, bax and Ki67 proteins in lymphomas of the mucosa-associated lymphoid tissue Anticancer Res 1998 18: 2403–2408

    CAS  PubMed  Google Scholar 

  40. Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D . Induction of WAF1/CIP1 by a p53-independent pathway Cancer Res 1994 54: 3391–3395

    CAS  PubMed  Google Scholar 

  41. Huang YQ, Li JJ, Karpatkin S . Thrombin inhibits tumor cell growth in association with up-regulation of p21 (waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway J Biol Chem 2000 275: 6462–6468

    Article  CAS  PubMed  Google Scholar 

  42. Sanchez-Beato M, Sáez AI, Martínez-Montero JC, Mateo MS, Sánchez-Verde L, Villuendas R, Troncone G, Piris MA . Cyclin-dependent kinase inhibitor p27Kip1 in lymphoid tissue: p27Kip1 expression is inversely proportional to the proliferative index Am J Pathol 1997 151: 151–160

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Quintanilla-Martínez L, Thieblemont C, Fend F, Kumar S, Pinyol M, Campo E, Jaffe ES, Raffeld M . Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor Am J Pathol 1998 153: 175–182

    Article  PubMed  PubMed Central  Google Scholar 

  44. Erlanson M, Portin C, Linderholm B, Lindh J, Roos G, Landberg G . Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications Blood 1998 92: 770–777

    CAS  PubMed  Google Scholar 

  45. Vrhovac R, Delmer A, Tang R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F . Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia Blood 1998 91: 4694–4700

    CAS  PubMed  Google Scholar 

  46. Chiarle R, Budel LM, Skolnik J, Frizzera G, Chilosi M, Corato A, Pizzolo G, Magidson J, Montagnoli A, Pagano M, Maes B, De Wolf-Peeters C, Inghirami G . Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma Blood 2000 95: 619–626

    CAS  PubMed  Google Scholar 

  47. Saez A, Sanchez E, Sanchez-Beato M, Cruz MA, Chacon I, Muñoz E, Camacho FI, Martinez-Montero JC, Mollejo M, Garcia JF, Piris MA . p27Kip1 is abnormally expressed in diffuse large B-cell lymphomas and is associated with an adverse clinical outcome Br J Cancer 1999 80: 1427–1434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Park M, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C, Koff A . P27 and Rb are on overlapping pathways suppressing tumorigenesis in mice Proc Natl Acad Sci USA 1999 96: 6382–6387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ginsberg AM, Raffeld M, Cossman J . Inactivation of the retinoblastoma gene in human lymphoid neoplasms Blood 1991 77: 833–840

    CAS  PubMed  Google Scholar 

  50. Jares P, Campo E, Pinyol M, Bosch F, Miquel R, Fernández PL, Sánchez-Beato M, Soler F, Pérez-Losada A, Nayach I, Mallofre C, Piris MA, Montserrat E, Cardesa A . Expression of retinoblastoma gene product (pRb) in mantle cell lymphomas. Correlation with cyclin D1 (PRAD1/CCND1) mRNA levels and proliferative activity Am J Pathol 1996 148: 1591–1600

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Cuneo A, De Angeli C, Roberti MG, Piva N, Bigoni R, Gandini D, Rigolin GM, Moretti S, Cavazzini P, Del Senno L, Castoldi G . Richter's syndrome in a case of atypical chronic lymphocytic leukaemia with the t(11;14)(q13;q32): role for a p53 exon 7 gene mutation Br J Haematol 1996 92: 375–381

    Article  CAS  PubMed  Google Scholar 

  52. Levy V, Ugo V, Delmer A, Tang R, Ramond S, Perrot JY, Vehovac R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F . Cyclin D1 overexpression allows identification of an aggressive subset of leukemic lymphoproliferative disorder Leukemia 1999 13: 1343–1351

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by grants CICYT SAF 99/20, FIS 99/0189 and FIJC-01/P-EM. AM has a fellowship from Hospital Clínic. We thank Montse Sánchez and Irazema Nayach for the excellent technical assistance. MS was supported by Dako.

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  1. E Montserrat and E Campo: EM and EC share the senior authorship of this paper

Authors and Affiliations

  1. Department of Hematology, Institute of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain

    F Cobo, M Gómez, J Esteve, F Bosch, A López-Guillermo & E Montserrat

  2. Laboratory of Pathology, Hematopathology Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain

    A Martínez, M Pinyol, L Hernández, S Beá, M Rozman & E Campo

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Cobo, F., Martínez, A., Pinyol, M. et al. Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia. Leukemia 16, 1028–1034 (2002). https://doi.org/10.1038/sj.leu.2402529

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