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Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course

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Abstract

Translocations involving MYC are rare in chronic lymphocytic leukemia (CLL), and up to now, their prognostic significance remains unclear. We report the characteristics of 21 patients with CLL and nine patients with prolymphocytic leukemia (PLL), diagnosed in multiple centers (n = 13), which showed an MYC translocation demonstrated by fluorescence in situ hybridization. The prevalence was estimated to be <1%. Advanced age and male predominance were observed. Morphological analysis frequently revealed the presence of prolymphocytes. A typical “CLL-immunophenotype” was found in four of nine cases with PLL. Moreover, CD5 and CD23 were frequently expressed in PLL. The latter findings are atypical for PLL and may suggest transformation or progression of an underlying CLL. MYC translocations were frequently observed with concomitant adverse cytogenetic markers, such as del(11q) (n = 8/30) and/or del(17p)/monosomy 17 (n = 7/30). In addition, the presence of unbalanced translocations (n = 24 in 13/30 cases) and complex karyotype (n = 16/30) were frequent in cases with MYC translocations. Altogether, del(17p)/monosomy 17, del(11q), and/or complex karyotype were observed in 22 of 30 patients. Survival outcome was poor: the median time to treatment was only 5 months, and overall survival (OS) from clinical diagnosis and from genetic detection was 71 and 19 months, respectively. In conclusion, CLL/PLL with MYC translocations is a rare entity, which seems to be associated with adverse prognostic features and unfavorable outcome.

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References

  1. Binet JL, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G, Dohner H, Hallek M, Hillmen P, Keating M, Montserrat E, Kipps TJ, Rai K (2006) Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 107:859–861

    Article  PubMed  CAS  Google Scholar 

  2. Van Den Neste E, Robin V, Francart J, Hagemeijer A, Stul M, Vandenberghe P, Delannoy A, Sonet A, Deneys V, Costantini S, Ferrant A, Robert A, Michaux L (2007) Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine. Leukemia 21:1715–1722

    Article  Google Scholar 

  3. Dicker F, Schnittger S, Haferlach T, Kern W, Schoch C (2006) Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression. Blood 108:3152–3160

    Article  PubMed  CAS  Google Scholar 

  4. Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R, Hallek M, Wendtner CM (2006) Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood 107:742–751

    Article  PubMed  CAS  Google Scholar 

  5. Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, Roman E, Jack A (2010) Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 28:3360–3365

    Article  PubMed  CAS  Google Scholar 

  6. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109:3489–3495

    Article  PubMed  CAS  Google Scholar 

  7. Obermann EC, Csato M, Dirnhofer S, Tzankov A (2009) Aberrations of the MYC gene in unselected cases of diffuse large B-cell lymphoma are rare and unpredictable by morphological or immunohistochemical assessment. J Clin Pathol 62:754–756

    Article  PubMed  CAS  Google Scholar 

  8. Huh YO, Lin KI, Vega F, Schlette E, Yin CC, Keating MJ, Luthra R, Medeiros LJ, Abruzzo LV (2008) MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis. Br J Haematol 142:36–44

    Article  PubMed  Google Scholar 

  9. Mitelman F, Johansson B, Mertens F (eds) (2010) Mitelman database of chromosome aberrations and gene fusions in cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman

  10. Klapproth K, Wirth T (2010) Advances in the understanding of MYC-induced lymphomagenesis. Br J Haematol 149:484–497

    Article  PubMed  CAS  Google Scholar 

  11. Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, Courel MN, Ruminy P, Picquenot JM, Tilly H (2007) Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. Leukemia 21:515–523

    Article  PubMed  CAS  Google Scholar 

  12. Nowakowski GS, Dewald GW, Hoyer JD, Paternoster SF, Stockero KJ, Fink SR, Smoley SA, Remstein ED, Phyliky RL, Call TG, Shanafelt TD, Kay NE, Zent CS (2005) Interphase fluorescence in situ hybridization with an IGH probe is important in the evaluation of patients with a clinical diagnosis of chronic lymphocytic leukaemia. Br J Haematol 130:36–42

    Article  PubMed  CAS  Google Scholar 

  13. Cavazzini F, Hernandez JA, Gozzetti A, Russo Rossi A, De Angeli C, Tiseo R, Bardi A, Tammiso E, Crupi R, Lenoci MP, Forconi F, Lauria F, Marasca R, Maffei R, Torelli G, Gonzalez M, Martin-Jimenez P, Maria Hernandez J, Rigolin GM, Cuneo A (2008) Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis. Br J Haematol 142:529–537

    Article  PubMed  Google Scholar 

  14. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1989) Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French–American–British (FAB) Cooperative Group. J Clin Pathol 42:567–584

    Article  PubMed  CAS  Google Scholar 

  15. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D (1994) The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 8:1640–1645

    PubMed  CAS  Google Scholar 

  16. Moreau EJ, Matutes E, A’Hern RP, Morilla AM, Morilla RM, Owusu-Ankomah KA, Seon BK, Catovsky D (1997) Improvement of the chronic lymphocytic leukemia scoring system with themonoclonal antibody SN8 (CD79b). Am J Clin Pathol 108:378–382

    PubMed  CAS  Google Scholar 

  17. Put N, Konings P, Rack K, Jamar M, Van Roy N, Libouton JM, Vannuffel P, Sartenaer D, Ameye G, Speleman F, Herens C, Poirel HA, Moreau Y, Hagemeijer A, Vandenberghe P, Michaux L (2009) Improved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: A Belgian multicentric study. Genes Chromosom Cancer 48:843–853

    Article  PubMed  CAS  Google Scholar 

  18. Brochet X, Lefranc MP, Giudicelli V (2008) IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res 36:W503–W508

    Article  PubMed  CAS  Google Scholar 

  19. Henglein B, Synovzik H, Groitl P, Bornkamm GW, Hartl P, Lipp M (1989) Three breakpoints of variant t(2;8) translocations in Burkitt’s lymphoma cells fall within a region 140 kilobases distal from c-myc. Mol Cell Biol 9:2105–2113

    PubMed  CAS  Google Scholar 

  20. R Development Core Team (2010) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  21. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, Rai KR (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87:4990–4997

    PubMed  CAS  Google Scholar 

  22. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:5446–5456

    Article  PubMed  CAS  Google Scholar 

  23. Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Guneo A, Knuutila S, Elonen E, Gahrton G (1990) Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 323:720–724

    Article  PubMed  CAS  Google Scholar 

  24. Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T (2007) Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia 21:2442–2451

    Article  PubMed  CAS  Google Scholar 

  25. Nowakowski GS, Smoley S, Schwager S, Zent CS, Call TG, Shanafelt TD, Hanson CA, Tschumper RC, Jelinek DF, Van Dyke DL, Kay NE (2007) Presence of immunoglobulin heavy chain gene (IGH) translocations in chronic lymphocytic leukemia is related to poor prognosis. ASH Annual Meeting Abstracts, vol 110, p. 2067

  26. Martin-Subero JI, Ibbotson R, Klapper W, Michaux L, Callet-Bauchu E, Berger F, Calasanz MJ, De Wolf-Peeters C, Dyer MJ, Felman P, Gardiner A, Gascoyne RD, Gesk S, Harder L, Horsman DE, Kneba M, Kuppers R, Majid A, Parry-Jones N, Ritgen M, Salido M, Sole F, Thiel G, Wacker HH, Oscier D, Wlodarska I, Siebert R (2007) A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation. Leukemia 21:1532–1544

    Article  PubMed  CAS  Google Scholar 

  27. Chapiro E, Radford-Weiss I, Bastard C, Luquet I, Lefebvre C, Callet-Bauchu E, Leroux D, Talmant P, Mozziconacci MJ, Mugneret F, Struski S, Raynaud S, Andrieux J, Barin C, Jotterand M, Mossafa H, Ramond S, Terre C, Lippert E, Berger F, Felman P, Merle-Beral H, Bernard OA, Davi F, Berger R, Nguyen-Khac F (2008) The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia. Leukemia 22:2123–2127

    Article  PubMed  CAS  Google Scholar 

  28. Put N, Meeus P, Chatelain B, Rack K, Boeckx N, Nollet F, Graux C, Van Den Neste E, Janssens A, Madoe V, Van Hoof A, Bilhou-Nabera C, Wlodarska I, Vandenberghe P, Michaux L (2009) Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia. Leukemia 23:1201–1204

    Article  PubMed  CAS  Google Scholar 

  29. Delgado M, León J (2010) Myc roles in hematopoiesis and leukemia. Genes & Cancer 1:605–616

    Article  CAS  Google Scholar 

  30. Zhang W, Kater AP, Widhopf GF 2nd, Chuang HY, Enzler T, James DF, Poustovoitov M, Tseng PH, Janz S, Hoh C, Herschman H, Karin M, Kipps TJ (2010) B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 107:18956–18960

    Article  PubMed  CAS  Google Scholar 

  31. Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL (2004) The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl) 13:279–287

    Article  CAS  Google Scholar 

  32. Merchant S, Schlette E, Sanger W, Lai R, Medeiros LJ (2003) Mature B-cell leukemias with more than 55% prolymphocytes: report of 2 cases with Burkitt lymphoma-type chromosomal translocations involving c-myc. Arch Pathol Lab Med 127:305–309

    PubMed  Google Scholar 

  33. Kroft SH, Dawson DB, McKenna RW (2001) Large cell lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. A flow cytometric analysis of seven cases. Am J Clin Pathol 115:385–395

    Article  PubMed  CAS  Google Scholar 

  34. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916

    Article  PubMed  Google Scholar 

  35. Lau LC, Lim P, Lim YC, Teng LM, Lim TH, Lim LC, Tan SY, Lim ST, Sanger WG, Tien SL (2008) Occurrence of trisomy 12, t(14;18)(q32;q21), and t(8;14)(q24.1;q11.2) in a patient with B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 185:95–101

    Article  PubMed  CAS  Google Scholar 

  36. Lens D, Coignet LJ, Brito-Babapulle V, Lima CS, Matutes E, Dyer MJ, Catovsky D (1999) B cell prolymphocytic leukaemia (B-PLL) with complex karyotype and concurrent abnormalities of the p53 and c-MYC gene. Leukemia 13:873–876

    Article  PubMed  CAS  Google Scholar 

  37. Maclean KH, Kastan MB, Cleveland JL (2007) Atm deficiency affects both apoptosis and proliferation to augment Myc-induced lymphomagenesis. Mol Cancer Res 5:705–711

    Article  PubMed  CAS  Google Scholar 

  38. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13:2658–2669

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the following clinicians, cytogeneticists, and clinical biologists for kindly providing clinical and cytogenetic data and material for morphological and cytogenetic assessment: G. Ameye, T. Braeckevelt, A. Delannoy, A. Janssens, F. Lacquet, J.-M. Libouton, V. Maertens, B. Maes, F. Nollet, P. Saussoy, J.-M. Scheiff, N. Straetmans, M. Van den Driessche, E. Van Den Neste, A. Van Hoof. We gratefully acknowledge H. Lemmens, M. Stul, H. Vranckx, W. De Kelver, and all laboratory technicians for excellent technical assistance. We are also indebted to A. Ferrant for critical reading of this manuscript and to R. Logist for clerical assistance.

Funding

This work was supported by Stichting tegen Kanker. N. Put is supported by Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen. P. Konings and Y. Moreau are supported by grants Katholieke Universiteit Leuven (KUL) Geconcerteerde Onderzoeksacties Mathematical engineering tools for Networks (GOA MaNet), KUL Center of Excellence Symbiosys–KUL Center for Computational Systems Biology (CoE EF/05/007), Belgian Science Policy Interuniversitaire Attractiepolen P6/25 (BelSPO IUAP P6/25), Agentschap voor Innovatie door Wetenschap en Technologie (IWT) Strategisch Basisonderzoek–Molecular Karyotyping (SBO-MoKA), Federale Overheidsdienst (FOD)–Cancer. P. Vandenberghe is a senior clinical investigator of FWO Vlaanderen.

Disclosures about potential conflict of interest

There is no conflict of interest to declare for this study.

Author information

Authors and Affiliations

  1. Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000, Leuven, Belgium

    Natalie Put, Katrien Van Roosbroeck, Peter Meeus, Iwona Wlodarska, Anne Hagemeijer, Peter Vandenberghe & Lucienne Michaux

  2. Department of Electrical Engineering/IBBT-K.U. Leuven Future Health Department, Catholic University of Leuven, Leuven, Belgium

    Peter Konings & Yves Moreau

  3. Department of Clinical Biology, O.L.V. Ziekenhuis, Aalst, Belgium

    Peter Meeus

  4. Department of Clinical Biology, University Hospital Leuven, Leuven, Belgium

    Caroline Brusselmans

  5. Center for Human Genetics, Institut de Pathologie et de Génétique, Gosselies, Belgium

    Katrina Rack

  6. Laboratoire de Cytogénétique, CHU de Hautepierre, Strasbourg, France

    Carine Gervais

  7. Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris, France

    Florence Nguyen-Khac & Elise Chapiro

  8. INSERM UMRS872, Université Pierre et Marie Curie, Paris, France

    Florence Nguyen-Khac & Elise Chapiro

  9. Laboratoire de Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France

    Isabelle Radford-Weiss

  10. Génétique des Hémopathies, CHU Toulouse, Toulouse, France

    Stéphanie Struski & Nicole Dastugue

  11. Laboratoire de Cytogénétique, CHU Limoges, Limoges, France

    Nathalie Gachard

  12. Laboratoire de Cytogénétique, CHU Grenoble, Grenoble, France

    Christine Lefebvre

  13. Laboratoire de Cytogénétique, CHU Tours, Tours, France

    Carole Barin

  14. Hématologie biologique, Hôpital Avicenne, Bobigny, France

    Virginie Eclache

  15. Laboratoire de Cytogénétique, Hôpital de Chambéry, Chambéry, France

    Sandra Fert-Ferrer

  16. Département de Biopathologie, Institut Paoli-Calmettes, Marseille, France

    Sophy Laibe & Marie-Joëlle Mozziconacci

  17. Laboratoire Biomnis, Lyon, France

    Benoît Quilichini

  18. Center for Human Genetics, Université catholique de Louvain, Brussels, Belgium

    Hélène A. Poirel

  19. Department of Hematology, University Hospital Saint-Luc, Brussels, Belgium

    Lucienne Michaux

Authors
  1. Natalie Put
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  2. Katrien Van Roosbroeck
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  21. Hélène A. Poirel
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  26. Lucienne Michaux
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Correspondence to Lucienne Michaux.

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Put, N., Van Roosbroeck, K., Konings, P. et al. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course. Ann Hematol 91, 863–873 (2012). https://doi.org/10.1007/s00277-011-1393-y

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