Clinical and Translational Oncology

, Volume 11, Issue 4, pp 194–198 | Cite as

Genetic alterations in chronic lymphocytic leukaemia

Educational Series Molecular and Cellular Biology of Cancer

Abstract

Chronic lymphocytic leukaemia (CLL), the commonest form of leukaemia in adults in Western countries, is a genetically heterogeneous disease. The most frequent genetic alterations are deletions in 13q14, 17p13 (TP53) and 11q22–q23 (ATM), and trisomy of chromosome 12. Furthermore, additional alterations have been described. The most relevant techniques used for detection of genetic alterations in CLL include comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH). Recently, PCR-based techniques, such as multiplex ligation-dependent probe amplification (MLPA), have been used to detect genetic alterations in CLL. This review summarises the genetic alterations described in CLL and the techniques used for their detection.

Keywords

Chronic lymphocytic leukaemia TP53 ATM MicroRNAs FISH MLPA 

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References

  1. 1.
    Dighiero G, Hamblin TJ (2008) Chronic lymphocytic leukaemia. Lancet 371:1017–1029PubMedCrossRefGoogle Scholar
  2. 2.
    Dohner H, Stilgenbauer S, Benner A et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916PubMedCrossRefGoogle Scholar
  3. 3.
    Seiler T, Dohner H, Stilgenbauer S (2006) Risk stratification in chronic lymphocytic leukemia. Semin Oncol 33:186–194PubMedCrossRefGoogle Scholar
  4. 4.
    Juliusson G, Oscier DG, Fitchett M et al (1990) Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 323:720–724PubMedGoogle Scholar
  5. 5.
    Stilgenbauer S, Bullinger L, Lichter P et al (2002) Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia 16:993–1007PubMedCrossRefGoogle Scholar
  6. 6.
    Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949PubMedCrossRefGoogle Scholar
  7. 7.
    Calin GA, Ferracin M, Cimmino A et al (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801PubMedCrossRefGoogle Scholar
  8. 8.
    Neilson JR, Auer R, White D et al (1997) Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia 11:1929–1932PubMedCrossRefGoogle Scholar
  9. 9.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310PubMedCrossRefGoogle Scholar
  10. 10.
    Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedCrossRefGoogle Scholar
  11. 11.
    Stankovic T, Weber P, Stewart G et al (1999) Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 353:26–29PubMedCrossRefGoogle Scholar
  12. 12.
    Bullrich F, Rasio D, Kitada S et al (1999) ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res 59:24–27PubMedGoogle Scholar
  13. 13.
    Schaffner C, Stilgenbauer S, Rappold GA et al (1999) Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 94:748–753PubMedGoogle Scholar
  14. 14.
    Pettitt AR, Sherrington PD, Stewart G et al (2001) p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation. Blood 98:814–822PubMedCrossRefGoogle Scholar
  15. 15.
    Coll-Mulet L, Iglesias-Serret D, Santidrian AF et al (2006) MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 107:4109–4114PubMedCrossRefGoogle Scholar
  16. 16.
    Austen B, Powell JE, Alvi A et al (2005) Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 106:3175–3182PubMedCrossRefGoogle Scholar
  17. 17.
    Austen B, Skowronska A, Baker C et al (2007) Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. J Clin Oncol 25:5448–5457PubMedCrossRefGoogle Scholar
  18. 18.
    Sturm I, Bosanquet AG, Hermann S et al (2003) Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ 10:477–484PubMedCrossRefGoogle Scholar
  19. 19.
    el Rouby S, Thomas A, Costin D et al (1993) p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452–3459PubMedGoogle Scholar
  20. 20.
    Gaidano G, Ballerini P, Gong JZ et al (1991) p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 88:5413–5417PubMedCrossRefGoogle Scholar
  21. 21.
    Wattel E, Preudhomme C, Hecquet B et al (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148–3157PubMedGoogle Scholar
  22. 22.
    Dohner H, Fischer K, Bentz M et al (1995) p53 gene deletion predicts for poor survival and nonresponse to therapy with purine analogs in chronic B-cell leukemias. Blood 85:1580–1589PubMedGoogle Scholar
  23. 23.
    Lens D, Dyer MJ, Garcia-Marco JM et al (1997) p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis. Br J Haematol 99:848–857PubMedCrossRefGoogle Scholar
  24. 24.
    Silber R, Degar B, Costin D et al (1994) Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs. Blood 84:3440–3446PubMedGoogle Scholar
  25. 25.
    Cordone I, Masi S, Mauro FR et al (1998) p53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis. Blood 91:4342–4349PubMedGoogle Scholar
  26. 26.
    Thornton PD, Gruszka-Westwood AM, Hamoudi RA et al (2004) Characterisation of TP53 abnormalities in chronic lymphocytic leukaemia. Hematol J 5:47–54PubMedCrossRefGoogle Scholar
  27. 27.
    Rossi D, Cerri M, Deambrogi C et al (2009) The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res 15:995–1004PubMedCrossRefGoogle Scholar
  28. 28.
    Tsimberidou AM, Keating MJ (2006) Richter’s transformation in chronic lymphocytic leukemia. Semin Oncol 33:250–256PubMedCrossRefGoogle Scholar
  29. 29.
    Matutes E, Oscier D, Garcia-Marco J et al (1996) Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 92:382–388PubMedCrossRefGoogle Scholar
  30. 30.
    Kienle DL, Korz C, Hosch B et al (2005) Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes. J Clin Oncol 23:3780–3792PubMedCrossRefGoogle Scholar
  31. 31.
    Tsujimoto Y, Yunis J, Onorato-Showe L et al (1984) Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224:1403–1406PubMedCrossRefGoogle Scholar
  32. 32.
    Cuneo A, Rigolin GM, Bigoni R et al (2004) Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis. Leukemia 18:476–483PubMedCrossRefGoogle Scholar
  33. 33.
    Merup M, Moreno TC, Heyman M et al (1998) 6q deletions in acute lymphoblastic leukemia and non-Hodgkin’s lymphomas. Blood 91:3397–3400PubMedGoogle Scholar
  34. 34.
    Rudenko HC, Else M, Dearden C et al (2008) Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescence in situ hybridisation and array-based comparative genomic hybridisation. Leuk Lymphoma 49:1879–1886PubMedCrossRefGoogle Scholar
  35. 35.
    Huh YO, Lin KI, Vega F et al (2008) MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis. Br J Haematol 142:36–44PubMedCrossRefGoogle Scholar
  36. 36.
    Rimokh R, Rouault JP, Wahbi K et al (1991) A chromosome 12 coding region is juxtaposed to the MYC protooncogene locus in a t(8;12)(q24;q22) translocation in a case of B-cell chronic lymphocytic leukemia. Genes Chromosomes Cancer 3:24–36PubMedCrossRefGoogle Scholar
  37. 37.
    Wang TY, Samples DM, Dabdoub R et al (1991) c-myc and K-ras-2 oncogenes in B-cell chronic lymphocytic leukemia with del(12)(p13). Cancer Genet Cytogenet 51:125–130PubMedCrossRefGoogle Scholar
  38. 38.
    Coll-Mulet L, Santidrian AF, Cosialls AM et al (2008) Multiplex ligation-dependent probe amplification for detection of genomic alterations in chronic lymphocytic leukaemia. Br J Haematol 142:793–801PubMedCrossRefGoogle Scholar
  39. 39.
    Vallat L, Magdelenat H, Merle-Beral H et al (2003) The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays. Blood 101:4598–4606PubMedCrossRefGoogle Scholar
  40. 40.
    Moshynska O, Sankaran K, Pahwa P et al (2004) Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia. J Natl Cancer Inst 96:673–682PubMedCrossRefGoogle Scholar
  41. 41.
    Iglesias-Serret D, Coll-Mulet L, Santidrian AF et al (2005) Re: Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia. J Natl Cancer Inst 97:1090–1091; author reply 1093–1095PubMedGoogle Scholar
  42. 42.
    Coenen S, Pickering B, Potter KN et al (2005) The relevance of sequence insertions in the Mcl-1 promoter in chronic lymphocytic leukemia and in normal cells. Haematologica 90:1285–1286PubMedGoogle Scholar
  43. 43.
    Tobin G, Skogsberg A, Thunberg U et al (2005) Mcl-1 gene promoter insertions do not correlate with disease outcome, stage or VH gene mutation status in chronic lymphocytic leukaemia. Leukemia 19:871–873PubMedCrossRefGoogle Scholar
  44. 44.
    Raval A, Tanner SM, Byrd JC et al (2007) Down-regulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129:879–890PubMedCrossRefGoogle Scholar
  45. 45.
    Raval A, Byrd JC, Plass C (2006) Epigenetics in chronic lymphocytic leukemia. Semin Oncol 33:157–166PubMedCrossRefGoogle Scholar
  46. 46.
    Gahrton G, Robert KH, Friberg K et al (1980) Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B0cell-mitogen stimulation. Blood 56:640–647PubMedGoogle Scholar
  47. 47.
    Hurley JN, Fu SM, Kunkel HG et al (1980) Chromosome abnormalities of leukaemic B lymphocytes in chronic lymphocytic leukaemia. Nature 283:76–78PubMedCrossRefGoogle Scholar
  48. 48.
    Bentz M, Huck K, du Manoir S et al (1995) Comparative genomic hybridization in chronic B-cell leukemias shows a high incidence of chromosomal gains and losses. Blood 85:3610–3618PubMedGoogle Scholar
  49. 49.
    Odero MD, Soto JL, Matutes E et al (2001) Comparative genomic hybridization and amplotyping by arbitrarily primed PCR in stage A B-CLL. Cancer Genet Cytogenet 130:8–13PubMedCrossRefGoogle Scholar
  50. 50.
    Schwaenen C, Nessling M, Wessendorf S et al (2004) Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci U S A 101:1039–1044PubMedCrossRefGoogle Scholar
  51. 51.
    Sargent R, Jones D, Abruzzo LV et al (2009) Customized oligonucleotide array-based comparative genomic hybridization as a clinical assay for genomic profiling of chronic lymphocytic leukemia. J Mol Diagn 11:25–34PubMedCrossRefGoogle Scholar
  52. 52.
    Novak U, Oppliger Leibundgut E, Hager J et al (2002) A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL). Blood 100:1787–1794PubMedGoogle Scholar
  53. 53.
    Dicker F, Schnittger S, Haferlach T et al (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 108:3152–3160PubMedCrossRefGoogle Scholar
  54. 54.
    Mayr C, Speicher MR, Kofler DM et al (2006) Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood 107:742–751PubMedCrossRefGoogle Scholar
  55. 55.
    Grubor V, Krasnitz A, Troge JE et al (2009) Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA). Blood 113:1294–1303PubMedCrossRefGoogle Scholar
  56. 56.
    Dohner H, Stilgenbauer S, Dohner K et al (1999) Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis. J Mol Med 77:266–281PubMedCrossRefGoogle Scholar
  57. 57.
    Shanafelt TD, Jelinek D, Tschumper R et al (2006) Cytogenetic abnormalities can change during the course of the disease process in chronic lymphocytic leukemia. J Clin Oncol 24:3218–3219; author reply 3219–3220PubMedCrossRefGoogle Scholar
  58. 58.
    Buijs A, Krijtenburg PJ, Meijer E (2006) Detection of risk-identifying chromosomal abnormalities and genomic profiling by multiplex ligation-dependent probe amplification in chronic lymphocytic leukemia. Haematologica 91:1434–1435PubMedGoogle Scholar
  59. 59.
    Bastard C, Raux G, Fruchart C et al (2007) Comparison of a quantitative PCR method with FISH for the assessment of the four aneuploidies commonly evaluated in CLL patients. Leukemia 21:1460–1463PubMedCrossRefGoogle Scholar
  60. 60.
    Sellner LN, Taylor GR (2004) MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat 23:413–419PubMedCrossRefGoogle Scholar
  61. 61.
    Di Bernardo MC, Crowther-Swanepoel D, Broderick P et al (2008) A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 40:1204–1210PubMedCrossRefGoogle Scholar
  62. 62.
    Enjuanes A, Benavente Y, Bosch F et al (2008) Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia. Cancer Res 68:10178–10101PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  1. 1.Departament de Ciències Fisiològiques IIIDIBELL-Universitat de Barcelona Campus de BellvitgeL’Hospitalet de LlobregatSpain

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