Skip to main content
SpringerLink
Log in

Molecular Biology of Chronic Lymphocytic Leukemia

  • Chapter
Chronic Lymphocytic Leukemia

Part of the book series: Contemporary Hematology ((CH))

Abstract

Discoveries in molecular biology are occurring rapidly, highlighted by new laboratory techniques, computers, and the sequencing of the human genome. These discoveries will shed new light on the etiology of diseases and the mechanisms that determine their clinical behavior. They will also help explain the diversity in disease progression and response to treatment and identify new therapeutic targets with the ultimate goal of cure.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Juliusson G, Oscier DG, Fitchett M, et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990; 323: 720–724.

    Article  PubMed  CAS  Google Scholar 

  2. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  PubMed  CAS  Google Scholar 

  3. Chapman RM, Corcoran MM, Gardiner A, Hawthorn LA, Cowell JK, Oscier DG. Frequent homozygous deletions of the Dl 3S25 locus in chromosome region 13q14 defines the location of a gene critical in leukaemogenesis in chronic B-cell lymphocytic leukaemia. Oncogene 1994; 9: 1289–1293.

    PubMed  CAS  Google Scholar 

  4. Jabbar SA, Ganeshaguru K, Wickremasinghe RG, Hoffbrand AV, Foroni L. Deletion of chromosome 13 (band q 14) but not trisomy 12 is a clonal event in B-chronic lymphocytic leukaemia (CLL). Br J Haematol 1995; 90: 476–478.

    Article  PubMed  CAS  Google Scholar 

  5. Garcia-Marco JA, Price CM, Catovsky D. Interphase cytogenetics in chronic lymphocytic leukemia. Cancer Genet Cytogenet 1997; 94: 52–58.

    Article  PubMed  CAS  Google Scholar 

  6. Cuneo A, Bigoni R, Rigolin GM, et al. 13814 deletion in non-Hodgkin’s lymphoma: correlation with clinico-pathologic features. Haematologica 1999; 84: 589–593.

    PubMed  CAS  Google Scholar 

  7. Cuneo A, Bigoni R, Rigolin GM, et al. Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features. Blood 1999; 93: 1372–1380.

    PubMed  CAS  Google Scholar 

  8. Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 1995; 82: 41–49.

    Article  PubMed  CAS  Google Scholar 

  9. Avet-Louseau H, Daviet A, Sauner S, Bataille R. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 2000; 111: 1116–1117.

    Article  PubMed  CAS  Google Scholar 

  10. Zojer N, Konigsberg R, Ackermann J, et al. Deletion of 13814 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000; 95: 1925–1930.

    PubMed  CAS  Google Scholar 

  11. Knuutila S, Teerenhovi L, Larramendy ML, et al. Cell lineage involvement of recurrent chromosomal abnormalities in hematologic neoplasms. Genes Chromosomes Cancer 1994; 10: 95–102.

    Article  PubMed  CAS  Google Scholar 

  12. Brown AG, Ross FM, Dunne EM, Steel CM, Weir-Thompson EM. Evidence for a new tumour suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene. Nat Genet 1993; 3: 67–72.

    Article  PubMed  CAS  Google Scholar 

  13. Hawthorn LA, Chapman R, Oscier D, Cowell JK. The consistent 13q14 translocation breakpoint seen in chronic B-cell leukaemia (BCLL) involves deletion of the D13S25 locus which lies distal to the retinoblastoma predisposition gene. Oncogene 1993; 8: 1415–1419.

    PubMed  CAS  Google Scholar 

  14. Liu Y, Szekely L, Grander D, et al. Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB 1 gene: evidence for a role of an adjacent locus. Proc Natl Acad Sci U S A 1993; 90: 8697–8701.

    Article  PubMed  CAS  Google Scholar 

  15. Hawthorn L, Roberts T, Verlind E, Kooy RF, Cowell JK. A yeast artificial chromosome contig that spans the RB 1-D 13531 interval on human chromosome 13 and encompasses the frequently deleted region in B-cell chronic lymphocytic leukemia. Genomics 1995; 30: 425–430.

    Article  PubMed  CAS  Google Scholar 

  16. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–330.

    Article  PubMed  CAS  Google Scholar 

  17. Bouyge-Moreau I, Rondeau G, Avet-Loiseau H, et al. Construction of a 780-kb PAC, BAC, and cosmid contig encompassing the minimal critical deletion involved in B cell chronic lymphocytic leukemia at 13q14.3. Genomics 1997; 46: 183–190.

    Article  PubMed  CAS  Google Scholar 

  18. Corcoran MM, Rasool O, Liu Y, et al. Detailed molecular delineation of 13g14.3 loss in B-cell chronic lymphocytic leukemia. Blood 1998; 91: 1382–1390.

    PubMed  CAS  Google Scholar 

  19. Stilgenbauer S, Nickolenko J, Wilhelm J, et al. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene 1998; 16: 1891–1897.

    Article  PubMed  CAS  Google Scholar 

  20. Liu Y, Corcoran M, Rasool O, et al. Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13814, frequently deleted in chronic lymphocytic leukemia. Oncogene 1997; 15: 2463–2473.

    Article  PubMed  CAS  Google Scholar 

  21. Bezieau S, Devilder MC, Rondeau G, Cadoret E, Moisan JP, Moreau I. Assignment of 48 ESTs to chromosome 13 band q14.3 and expression pattern for ESTs located in the core region deleted in B-CLL. Genomics 1998; 52: 369–373.

    Article  PubMed  CAS  Google Scholar 

  22. Kapanadze B, Kashuba V, Baranova A, et al. A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukemia and identification of a new putative tumor suppressor gene, LeuS. FEBS Lett 1998; 426: 266–270.

    Article  PubMed  CAS  Google Scholar 

  23. Mabuchi H, Fujii H, Calin G, et al. Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res 2001; 61: 2870–2877.

    PubMed  CAS  Google Scholar 

  24. Bullrich F, Fujii H, Calin G, et al. Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene. Cancer Res 2001; 61: 6640–6648.

    PubMed  CAS  Google Scholar 

  25. Wolf S, Mertens D, Schaffner C, et al. B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13814 comprises more than 560 kb covering all critical regions. Hum Mol Genet 2001; 10: 1275–1285.

    Article  PubMed  CAS  Google Scholar 

  26. Sossey-Alaoui K, Kitamura E, Head K, Cowell JK. Characterization of FAM10A4, a member of the ST 13 tumor suppressor gene family that maps to the 13q14.3 region associated with B-cell leukemia, multiple myeloma, and prostate cancer. Genomics 2002; 80: 5–7.

    Article  PubMed  CAS  Google Scholar 

  27. Kitamura E, Su G, Sossey-Alaoui K, et al. A transcription map of the minimally deleted region from 13814 in B-cell chronic lymphocytic leukemia as defined by large scale sequencing of the 650 kb critical region. Oncogene 2000; 19: 5772–5780.

    Article  PubMed  CAS  Google Scholar 

  28. Rondeau G, Moreau I, Bezieau S, Cadoret E, Moisan JP, Devilder MC. Exclusion of Leul and Leu2 genes as tumor suppressor genes in 13g14.3-deleted B-CLL. Leukemia 1999; 13: 1630–1632.

    Article  PubMed  CAS  Google Scholar 

  29. Neilson JR, Auer R, White D, et al. Deletions at l lq identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia 1997; 11: 1929–1932.

    Article  PubMed  CAS  Google Scholar 

  30. Hogan WJ, Tefferi A, Borell TJ, Jenkins R, Li CY, Witzig TE. Prognostic relevance of monosomy at the 13g14 locus detected by fluorescence in situ hybridization in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1999; 110: 77–81.

    Article  PubMed  CAS  Google Scholar 

  31. D’Arena G, Musto P, Cascavilla N, et al. CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2001; 42: 109–114.

    Article  PubMed  Google Scholar 

  32. Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100: 1410–146.

    PubMed  CAS  Google Scholar 

  33. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 2002; 100: 1177–1184.

    PubMed  CAS  Google Scholar 

  34. Gahrton G, Robert KH, Friberg K, Zech L, Bird AG. Extra chromosome 12 in chronic lymphocytic leukaemia. Lancet 1980; 1: 146–147.

    Article  PubMed  CAS  Google Scholar 

  35. Sadamori N, Han T, Minowada J, Cohen E, Sandberg AA. Chromosome studies in stimulated lymphocytes of B-cell chronic lymphocytic leukemias. Hematol Oncol 1983; 1: 243–250.

    Article  PubMed  CAS  Google Scholar 

  36. Han T, Sadamori N, Ozer H, et al. Cytogenetic studies in 77 patients with chronic lymphocytic leukemia: correlations with clinical, immunologic, and phenotypic data. J Clin Oncol 1984; 2: 1121–1132.

    PubMed  CAS  Google Scholar 

  37. Losada AP, Wessman M, Tiainen M, et al. Trisomy 12 in chronic lymphocytic leukemia: an interphase cytogenetic study. Blood 1991; 78: 775–779.

    PubMed  CAS  Google Scholar 

  38. Anastasi J, Le Beau MM, Vardiman JW, Fernald AA, Larson RA, Rowley JD. Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method. Blood 1992; 79: 1796–1801.

    PubMed  CAS  Google Scholar 

  39. Raghoebier S, Kibbelaar RE, Kleiverda JK, et al. Mosaicism of trisomy 12 in chronic lymphocytic leukemia detected by non-radioactive in situ hybridization. Leukemia 1992; 6: 1220–1226.

    PubMed  CAS  Google Scholar 

  40. Cuneo A, Wlodarska I, Sayed Aly M, et al. Non-radioactive in situ hybridization for the detection and monitoring of trisomy 12 in B-cell chronic lymphocytic leukaemia. Br J Haematol 1992; 81: 192–196.

    Article  PubMed  CAS  Google Scholar 

  41. Dohner H, Pohl S, Bulgay-Morschel M, Stilgenbauer S, Bentz M, Lichter P. Trisomy 12 in chronic lymphoid leukemias-a metaphase and interphase cytogenetic analysis. Leukemia 1993; 7: 516–20.

    PubMed  CAS  Google Scholar 

  42. Escudier SM, Pereira-Leahy JM, Drach JW, et al. Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia. Blood 1993; 81: 2702–2707.

    PubMed  CAS  Google Scholar 

  43. Crossen PE, Horn HL. Origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1987; 28: 185–186.

    Article  PubMed  CAS  Google Scholar 

  44. Einhorn S, Burvall K, Juliusson G, Gahrton G, Meeker T. Molecular analyses of chromosome 12 in chronic lymphocytic leukemia. Leukemia 1989; 3: 871–874.

    PubMed  CAS  Google Scholar 

  45. Dierlamm J, Wlodarska I, Michaux L, et al. FISH identifies different types of duplications with 12g13–15 as the commonly involved segment in B-cell lymphoproliferative malignancies characterized by partial trisomy 12. Genes Chromosomes Cancer 1997; 20: 155–166.

    Article  PubMed  CAS  Google Scholar 

  46. Chena C, Sarmiento M, Palacios MF, Scolnik M, Slavutsky I. Dup(12)(g13-q22) and 13q14 deletion in a case of B-cell chronic lymphocytic leukemia. Acta Haematol 2000; 104: 197–201.

    Article  PubMed  CAS  Google Scholar 

  47. Huang YQ, Raphael B, Buchbinder A, Li JJ, Zhang WG, Friedman-Kien AE. Rearrangement and expression of MDM2 oncogene in chronic lymphocytic leukemia. Am J Hematol 1994; 47: 139–141.

    Article  PubMed  CAS  Google Scholar 

  48. Merup M, Juliusson G, Wu X, et al. Amplification of multiple regions of chromosome 12, including 12g13–15, in chronic lymphocytic leukaemia. Eur J Haematol 1997; 58: 174–180.

    Article  PubMed  CAS  Google Scholar 

  49. Watanabe T, Hotta T, Ichikawa A, et al. The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin. Blood 1994; 84: 3158–3165.

    PubMed  CAS  Google Scholar 

  50. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.

    Article  PubMed  CAS  Google Scholar 

  51. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.

    Article  PubMed  CAS  Google Scholar 

  52. Gahn B, Schafer C, Neef J, et al. Detection of trisomy 12 and Rb-deletion in CD34+ cells of patients with B-cell chronic lymphocytic leukemia. Blood 1997; 89: 4275–4281.

    PubMed  CAS  Google Scholar 

  53. Gahn B, Schafer C, Neef J, et al. Detection of trisomy 12 in CD34+ progenitor cells in a patient with B-cell chronic lymphocytic leukemia by fluorescence in situ hybridization. Ann Oncol 1997; 8 (suppl 2): 55–57.

    Article  PubMed  Google Scholar 

  54. Gahn B, Wendenburg B, Troff C, et al. Analysis of progenitor cell involvement in B-CLL by simultaneous immunophenotypic and genotypic analysis at the single cell level. Br J Haematol 1999; 105: 955–959.

    Article  PubMed  CAS  Google Scholar 

  55. Han T, Ohtaki K, Sadamori N, et al. Cytogenetic evidence for clonal evolution in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1986; 23: 321–328.

    Article  PubMed  CAS  Google Scholar 

  56. Hjalmar V, Hast R, Kimby E. Sequential fluorescence in situ hybridization analyses for trisomy 12 in chronic leukemic B-cell disorders. Haematologica 2001; 86: 174–180.

    PubMed  CAS  Google Scholar 

  57. Criel A, Wlodarska I, Meeus P, et al. Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias. Br J Haematol 1994; 87: 523–528.

    Article  PubMed  CAS  Google Scholar 

  58. Cuneo A, Bigoni R, Balboni M, et al. Trisomy 12 in chronic lymphocytic leukemia and hairy cell leukemia: a cytogenetic and interphase cytogenetic study. Leuk Lymphoma 1994; 15: 167–172.

    Article  PubMed  CAS  Google Scholar 

  59. Garcia-Marco J, Matutes E, Morilla R, et al. Trisomy 12 in B-cell chronic lymphocytic leukaemia: assessment of lineage restriction by simultaneous analysis of immunophenotype and genotype in interphase cells by fluorescence in situ hybridization. Br J Haematol 1994; 87: 44–50.

    Article  PubMed  CAS  Google Scholar 

  60. Hjalmar V, Kimby E, Matutes E, et al. Trisomy 12 and lymphoplasmacytoid lymphocytes in chronic leukemic B-cell disorders. Haematologica 1998; 83: 602–609.

    PubMed  CAS  Google Scholar 

  61. Liso V, Capalbo S, Lapietra A, Pavone V, Guarini A, Specchia G. Evaluation of trisomy 12 by fluorescence in situ hybridization in peripheral blood, bone marrow and lymph nodes of patients with B-cell chronic lymphocytic leukemia. Haematologica 1999; 84: 212–217.

    PubMed  CAS  Google Scholar 

  62. Navarro B, Garcia-Marco JA, Jones D, Price CM, Catovsky D. Association and clonal distribution of trisomy 12 and 13q14 deletions in chronic lymphocytic leukaemia. Br J Haematol 1998; 102: 1330–1334.

    Article  PubMed  CAS  Google Scholar 

  63. Han T, Ozer H, Sadamori N, et al. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med 1984; 310: 288–292.

    Article  PubMed  CAS  Google Scholar 

  64. Sadamori N, Han T, Minowada J, Sandberg AA. Clinical significance of cytogenetic findings in untreated patients with B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1984; 11: 45–51.

    Article  PubMed  CAS  Google Scholar 

  65. Juliusson G, Gahrton G. Poor age-corrected survival of chronic lymphocytic leukaemia patients with trisomy 12. Eur J Haematol 1987; 38: 315–317.

    Article  PubMed  CAS  Google Scholar 

  66. Pittman S, Catovsky D. Prognostic significance of chromosome abnormalities in chronic lymphocytic leukaemia. Br J Haematol 1984; 58: 649–660.

    Article  PubMed  CAS  Google Scholar 

  67. Geisler CH, Philip P, Hansen MM. B-cell chronic lymphocytic leukaemia: clonal chromosome abnormalities and prognosis in 89 cases. Eur J Haematol 1989; 43: 397–403.

    Article  PubMed  CAS  Google Scholar 

  68. Han T, Sadamori N, Block AM, et al. Cytogenetic studies in chronic lymphocytic leukemia, prolymphocytic leukemia and hairy cell leukemia: a progress report. Nouv Rev Fr Hematol 1988; 30: 393–395.

    PubMed  CAS  Google Scholar 

  69. Que TH, Marco JG, Ellis J, et al. Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: analysis by stage, immunophenotype, and morphology. Blood 1993; 82: 571–575.

    PubMed  CAS  Google Scholar 

  70. Knauf WU, Knuutila S, Zeigmeister B, Thiel E. Trisomy 12 in B-cell chronic lymphocytic leukemia: correlation with advanced disease, atypical morphology, high levels of sCD25, and with refractoriness to treatment. Leuk Lymphoma 1995; 19: 289–294.

    Article  PubMed  CAS  Google Scholar 

  71. Matutes E, Oscier D, Garcia-Marco J, et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 1996; 92: 382–388.

    Article  PubMed  CAS  Google Scholar 

  72. Garcia-Marco JA, Price CM, Ellis J, et al. Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia. Leukemia 1996; 10: 1705–1711.

    PubMed  CAS  Google Scholar 

  73. Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997; 89: 4153–4160.

    PubMed  CAS  Google Scholar 

  74. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated 1g V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    PubMed  CAS  Google Scholar 

  75. Dohner H, Stilgenbauer S, James MR, et al. 1 lq deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997; 89: 2516–2522.

    PubMed  CAS  Google Scholar 

  76. Karhu R, Knuutila S, Kallioniemi OP, et al. Frequent loss of the 11q14–24 region in chronic lymphocytic leukemia: a study by comparative genomic hybridization. Tampere CLL Group. Genes Chromosomes Cancer 1997; 19: 286–290.

    Article  PubMed  CAS  Google Scholar 

  77. Nowell PC, Vonderheid EC, Besa E, Hoxie JA, Moreau L, Finan JB. The most common chromosome change in 86 chronic B cell or T cell tumors: a 14832 translocation. Cancer Genet Cytogenet 1986; 19: 219–227.

    Article  PubMed  CAS  Google Scholar 

  78. Gahrton G, Juliusson G. Clinical implication of chromosomal aberrations in chronic B-lymphocytic leukaemia cells. Nouv Rev Fr Hematol 1988; 30: 389–392.

    PubMed  CAS  Google Scholar 

  79. Koduru PR, Offit K, Filippa DA. Molecular analysis of breaks in BCL-1 proto-oncogene in B-cell lymphomas with abnormalities of 11q13. Oncogene 1989; 4: 929–934.

    PubMed  CAS  Google Scholar 

  80. Raffeld M, Jaffe ES. bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood 1991; 78: 259–263.

    PubMed  CAS  Google Scholar 

  81. Brizard F, Dreyfus B, Guilhot F, Tanzer J, Brizard A. 11g13 rearrangement in B cell chronic lymphocytic leukemia. Leuk Lymphoma 1997; 25: 539–543.

    PubMed  CAS  Google Scholar 

  82. Thieblemont C, Pack S, Sakai A, et al. Allelic loss of 11g13 as detected by MEN1-FISH is not associated with mutation of the MENI gene in lymphoid neoplasms. Leukemia 1999; 13: 85–91.

    Article  PubMed  CAS  Google Scholar 

  83. Stilgenbauer S, Liebisch P, James MR, et al. Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11g22.3–923.1 in lymphoproliferative disorders. Proc Natl Acad Sci USA 1996; 93:11, 837–11, 841.

    Article  CAS  Google Scholar 

  84. Stilgenbauer S, Schaffner C, Litterst A, et al. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med 1997; 3: 1155–119.

    Article  PubMed  CAS  Google Scholar 

  85. Vorechovsky I, Luo L, Dyer MJ, et al. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet 1997; 17: 96–99.

    Article  PubMed  CAS  Google Scholar 

  86. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268: 1749–1753.

    Article  PubMed  CAS  Google Scholar 

  87. Pandita TK. ATM function and telomere stability. Oncogene 2002; 21: 611–618.

    Article  PubMed  CAS  Google Scholar 

  88. Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev 1997; 11: 3471–3481.

    Article  PubMed  CAS  Google Scholar 

  89. Starostik P, Manshouri T, O’Brien S, et al. Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia. Cancer Res 1998; 58: 4552–4557.

    PubMed  CAS  Google Scholar 

  90. Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P. Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 1999; 94: 748–753.

    PubMed  CAS  Google Scholar 

  91. Stankovic T, Weber P, Stewart G, et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 1999; 353: 26–29.

    Article  PubMed  CAS  Google Scholar 

  92. Bullrich F, Rasio D, Kitada S, et al. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res 1999; 59: 24–27.

    PubMed  CAS  Google Scholar 

  93. Bevan S, Catovsky D, Marossy A, et al. Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia. Leukemia 1999; 13: 1497–1500.

    Article  PubMed  CAS  Google Scholar 

  94. Yuille MR, Condie A, Hudson CD, et al. ATM mutations are are in familial chronic lymphocytic leukemia. Blood 2002; 100: 603–609.

    Article  PubMed  CAS  Google Scholar 

  95. Kobayashi H, Espinosa R, 3rd, Fernald AA, et al. Analysis of deletions of the long arm of chromosome 11 in hematologic malignancies with fluorescence in situ hybridization. Genes Chromosomes Cancer 1993; 8: 246–252.

    Article  PubMed  CAS  Google Scholar 

  96. Sembries S, Pahl H, Stilgenbauer S, Dohner H, Schriever F. Reduced expression of adhesion molecules and cell signaling receptors by chronic lymphocytic leukemia cells with I lq deletion. Blood 1999; 93: 624–631.

    PubMed  CAS  Google Scholar 

  97. Lens D, Matutes E, Catovsky D, Coignet LJ. Frequent deletions at 11g23 and 13g14 in B cell prolymphocytic leukemia (B-PLL). Leukemia 2000; 14: 427–430.

    Article  PubMed  CAS  Google Scholar 

  98. Cuneo A, Bigoni R, Rigolin GM, et al. Late appearance of the 11g22.3–23.1 deletion involving the ATM locus in B-cell chronic lymphocytic leukemia and related disorders. Clinico-biological significance. Haematologica 2002; 87: 44–51.

    PubMed  CAS  Google Scholar 

  99. Fegan C, Robinson H, Thompson P, Whittaker JA, White D. Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of l lq and advanced or progressive disease. Leukemia 1995; 9: 2003–2008.

    PubMed  CAS  Google Scholar 

  100. Bigoni R, Cuneo A, Roberti MG, et al. Chromosome aberrations in atypical chronic lymphocytic leukemia: a cytogenetic and interphase cytogenetic study. Leukemia 1997; 11: 1933–1940.

    Article  PubMed  CAS  Google Scholar 

  101. Chevallier P, Penther D, Avet-Loiseau H, et al. CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukaemia. Br J Haematol 2002; 116: 142–150.

    Article  PubMed  CAS  Google Scholar 

  102. Callet-Bauchu E, Salles G, Gazzo S, et al. 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 /168.

    Google Scholar 

  103. Gaidano G, Ballerini P, Gong JZ, et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1991; 88: 5413–5417.

    Article  PubMed  CAS  Google Scholar 

  104. Fenaux P, Preudhomme C, Lai JL, et al. Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis. Leukemia 1992; 6: 246–250.

    PubMed  CAS  Google Scholar 

  105. Gandini D, Aguiari GL, Cuneo A, Piva R, Castoldi GL, del Senno L. Novel small deletions of the p53 gene in late-stage B-cell chronic lymphocytic leukaemia. Br J Haematol 1994; 88: 881–885.

    Article  PubMed  CAS  Google Scholar 

  106. Lens D, De Schouwer PJ, Hamoudi RA, et al. p53 abnormalities in B-cell prolymphocytic leukemia. Blood 1997; 89: 2015–2023.

    PubMed  CAS  Google Scholar 

  107. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991; 253: 49–53.

    Article  PubMed  CAS  Google Scholar 

  108. Zambetti GP, Levine AJ. A comparison of the biological activities of wild-type and mutant p53. FASEB J 1993; 7: 855–865.

    PubMed  CAS  Google Scholar 

  109. Harris CC. p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 1993;262:1980–1981.

    Google Scholar 

  110. el-Deiry WS. Regulation of p53 downstream genes. Semin Cancer Biol 1998; 8: 345–357.

    Article  PubMed  CAS  Google Scholar 

  111. el Rouby S, Bayona W, Pisharody SM, Newcomb EW. p53 mutations in B-cell chronic lymphocytic leukemia. Curr Top Microbiol Immunol 1992; 182: 313–317.

    Article  PubMed  Google Scholar 

  112. Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994; 84: 3148–3157.

    PubMed  CAS  Google Scholar 

  113. Lens D, Dyer MJ, Garcia-Marco JM, et al. p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis. Br J Haematol 1997; 99: 848–857.

    Article  PubMed  CAS  Google Scholar 

  114. Barnabas N, Shurafa M, Van Dyke DL, Wolman SR, Clark D, Worsham MJ. Significance of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients. Cancer 2001; 91: 285–293.

    Article  PubMed  CAS  Google Scholar 

  115. el Rouby S, Thomas A, Costin D, et al. p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 1993; 82: 3452–3459.

    PubMed  Google Scholar 

  116. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    PubMed  CAS  Google Scholar 

  117. Geisler CH, Philip P, Christensen BE, et al. In B-cell chronic lymphocytic leukaemia chromosome 17 abnor-malities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: acytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients. Leuk Res 1997; 21: 1011–1023.

    Article  PubMed  CAS  Google Scholar 

  118. Philip P, Geisler C, Hansen MM, et al. Aberrations of chromosome 6 in 193 newly diagnosed untreated cases of chronic lymphocytic leukemia. Cancer Genet Cytogenet 1991; 53: 35–43.

    Article  PubMed  CAS  Google Scholar 

  119. Glassman AB, Harper-Allen EA, Hayes KJ, Hopwood VL, Gutterman EE, Zagryn SP. Chromosome 6 abnormalities associated with prolymphocytic acceleration in chronic lymphocytic leukemia. Ann Clin Lab Sci 1998; 28: 24–29.

    PubMed  CAS  Google Scholar 

  120. Stilgenbauer S, Bullinger L, Benner A, et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia 1999; 13: 1331–1334.

    Article  PubMed  CAS  Google Scholar 

  121. Cuneo A, Roberti MG, Bigoni R, et al. Four novel non-random chromosome rearrangements in B-cell chronic lymphocytic leukaemia: 6p24–25 and 12p12–13 translocations, 4g21 anomalies and monosomy 21. BrJ Haematol 2000; 108: 559–564.

    Article  CAS  Google Scholar 

  122. Offit K, Parsa NZ, Gaidano G, et al. 6q deletions define distinct clinico-pathologic subsets of non-Hodgkin’s lymphoma. Blood 1993; 82: 2157–2162.

    PubMed  CAS  Google Scholar 

  123. Finn WG, Kay NE, Kroft SH, Church S, Peterson LC. Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients. Am J Hematol 1998; 59: 223–229.

    Article  PubMed  CAS  Google Scholar 

  124. Amiel A, Mulchanov I, Elis A, et al. Deletion of 6827 in chronic lymphocytic leukemia and multiple myeloma detected by fluorescence in situ hybridization. Cancer Genet Cytogenet 1999; 112: 53–56.

    Article  PubMed  CAS  Google Scholar 

  125. Demeter J, Porzsolt F, Rami sch S, Schmidt D, Schmid M, Messer G. Polymorphism of the tumour necrosis factor-alpha and lymphotoxin-alpha genes in chronic lymphocytic leukaemia. Br J Haematol 1997; 97: 107–112.

    Article  PubMed  CAS  Google Scholar 

  126. Oscier DG, Stevens J, Hamblin TJ, Pickering RM, Lambert R, Fitchett M. Correlation of chromosome abnormalities with laboratory features and clinical course in B-cell chronic lymphocytic leukaemia. Br J Haematol 1990; 76: 352–358.

    Article  PubMed  CAS  Google Scholar 

  127. Tsujimoto Y, Jaffe E, Cossman J, Gorham J, Nowell PC, Croce CM. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature 1985; 315: 340–343.

    Article  PubMed  CAS  Google Scholar 

  128. Hernandez JM, Mecucci C, Criel A, et al. Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria. Leukemia 1995; 9: 2140–2146.

    PubMed  CAS  Google Scholar 

  129. Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 1994; 91: 709–713.

    Article  PubMed  CAS  Google Scholar 

  130. Cuneo A, Bigoni R, Negrini M, et al. Cytogenetic and interphase cytogenetic characterization of atypical chronic lymphocytic leukemia carrying BCL1 translocation. Cancer Res 1997; 57: 1144–1150.

    PubMed  CAS  Google Scholar 

  131. Adachi M, Cossman J, Longo D, Croce CM, Tsujimoto Y. Variant translocation of the bc1–2 gene to immunoglobulin lambda light chain gene in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1989; 86: 2771–2774.

    Article  PubMed  CAS  Google Scholar 

  132. Adachi M, Tefferi A, Greipp PR, Kipps TJ, Tsujimoto Y. Preferential linkage of bc1–2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med 1990; 171: 559–564.

    Article  PubMed  CAS  Google Scholar 

  133. Ueshima Y, Bird ML, Vardiman JW, Rowley JD. A 14;19 translocation in B-cell chronic lymphocytic leukemia: a new recurring chromosome aberration. Int J Cancer 1985; 36: 287–290.

    PubMed  CAS  Google Scholar 

  134. Kerr LD, Duckett CS, Wamsley P, et al. The proto-oncogene bc1–3 encodes an I kappa B protein. Genes Dev 1992; 6: 2352–2363.

    Article  PubMed  CAS  Google Scholar 

  135. Michaux L, Mecucci C, Stul M, et al. BCL3 rearrangement and t(14;19)(q32;q13) in lymphoproliferative disorders. Genes Chromosomes Cancer 1996; 15: 38–47.

    Article  PubMed  CAS  Google Scholar 

  136. McKeithan TW, Takimoto GS, Ohno H, et al. BCL3 rearrangements and t(14;19) in chronic lymphocytic leukemia and other B-cell malignancies: a molecular and cytogenetic study. Genes Chromosomes Cancer 1997; 20: 64–72.

    Article  PubMed  CAS  Google Scholar 

  137. Juliusson G, Gahrton G. Chromosome aberrations in B-cell chronic lymphocytic leukemia. Pathogenetic and clinical implications. Cancer Genet Cytogenet 1990; 45: 143–160.

    Article  PubMed  CAS  Google Scholar 

  138. Virgilio L, Isobe M, Narducci MG, et al. Chromosome walking on the TCLI locus involved in T-cell neoplasia. Proc Natl Acad Sci USA 1993; 90: 9275–9279.

    Article  PubMed  CAS  Google Scholar 

  139. Virgilio L, Narducci MG, Isobe M, et al. Identification of the TCLI gene involved in T-cell malignancies. Proc Natl Acad Sci USA 1994;91:12, 530–12, 534.

    Article  CAS  Google Scholar 

  140. Narducci MG, Pescarmona E, Lazzeri C, et al. Regulation of TCLI expression in B- and T-cell lymphomas and reactive lymphoid tissues. Cancer Res 2000; 60: 2095–2100.

    PubMed  CAS  Google Scholar 

  141. Yuille MR, Condie A, Stone EM, et al. TCL1 is activated by chromosomal rearrangement or by hypomethylation. Genes Chromosomes Cancer 2001; 30: 336–341.

    Article  PubMed  CAS  Google Scholar 

  142. Bichi R, Shinton SA, Martin ES, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL 1 expression. Proc Natl Acad Sci U S A 2002; 99: 6955–6960.

    Article  PubMed  CAS  Google Scholar 

  143. Geisler CH, Larsen JK, Hansen NE, et al. Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia. Blood 1991; 78: 1795–1802.

    PubMed  CAS  Google Scholar 

  144. Rassenti LZ, Kipps TJ. Lack of allelic exclusion in B cell chronic lymphocytic leukemia. J Exp Med 1997; 185: 1435–1445.

    Article  PubMed  CAS  Google Scholar 

  145. Lewis CM, Pegrum GD. Autoinunune antibodies in chronic lymphatic leukaemia. Br J Haematol 1978; 38: 75–84.

    Article  PubMed  CAS  Google Scholar 

  146. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol 1986; 39: 713–716.

    Article  PubMed  CAS  Google Scholar 

  147. Broker BM, Klajman A, Youinou P, et al. Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies. J Autoimmun 1988; 1: 469–481.

    Article  PubMed  CAS  Google Scholar 

  148. Caligaris-Cappio F. B-chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood 1996; 87: 2615–2620.

    PubMed  CAS  Google Scholar 

  149. Kipps TJ, Tomhave E, Pratt LF, Duffy S, Chen PP, Carson DA. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1989; 86: 5913–5917.

    Article  PubMed  CAS  Google Scholar 

  150. Logtenberg T, Schutte ME, Inghirami G, et al. Immunoglobulin VH gene expression in human B cell lines and tumors: biased VH gene expression in chronic lymphocytic leukemia. Int Immunol 1989; 1: 362–366.

    Article  PubMed  CAS  Google Scholar 

  151. Mayer R, Logtenberg T, Strauchen J, et al. CD5 and immunoglobulin V gene expression in B-cell lymphomas and chronic lymphocytic leukemia. Blood 1990; 75: 1518–1524.

    PubMed  CAS  Google Scholar 

  152. Deane M, Baker BW, Norton JD. Immunoglobulin VH4 gene usage in B lymphoid leukaemias. Br J Haematol 1993; 84: 242–249.

    Article  PubMed  CAS  Google Scholar 

  153. Ebeling SB, Schutte ME, Logtenberg T. Molecular analysis of VH and VL regions expressed in IgG-bearing chronic lymphocytic leukemia (CLL): further evidence that CLL is a heterogeneous group of tumors. Blood 1993; 82: 1626–1631.

    PubMed  CAS  Google Scholar 

  154. Matolcsy A, Casali P, Nador RG, Liu YF, Knowles DM. Molecular characterization of IgA- and/or IgG-switched chronic lymphocytic leukemia B cells. Blood 1997; 89: 1732–1739.

    PubMed  CAS  Google Scholar 

  155. Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102: 1515–1525.

    Article  PubMed  CAS  Google Scholar 

  156. Korganow AS, Martin T, Weber JC, et al. Molecular analysis of rearranged VH genes during B cell chronic lymphocytic leukemia: intraclonal stability is frequent but not constant. Leuk Lymphoma 1994; 14: 55–69.

    Article  PubMed  CAS  Google Scholar 

  157. Aoki H, Takishita M, Kosaka M, Saito S. Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenstrom’s macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter’s syndrome but not in common CLL. Blood 1995; 85: 1913–1919.

    PubMed  CAS  Google Scholar 

  158. Schettino EW, Cerutti A, Chiorazzi N, Casali P. Lack of intraclonal diversification in Ig heavy and light chain V region genes expressed by CD5+IgM+ chronic lymphocytic leukemia B cells: a multiple time point analysis. J Immunol 1998; 160: 820–830.

    PubMed  CAS  Google Scholar 

  159. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    PubMed  CAS  Google Scholar 

  160. Thompson AA, Talley JA, Do HN, et al. Aberrations of the B-cell receptor B29 (CD79b) gene in chronic lymphocytic leukemia. Blood 1997; 90: 1387–1394.

    PubMed  CAS  Google Scholar 

  161. Thompson AA, Do HN, Saxon A, Wall R. Widespread B29 (CD79b) gene defects and loss of expression in chronic lymphocytic leukemia. Leuk Lymphoma 1999; 32: 561–569.

    PubMed  CAS  Google Scholar 

  162. Cragg MS, Chan HT, Fox MD, et al. The alternative transcript of CD79b is overexpressed in B-CLL and inhibits signaling for apoptosis. Blood 2002; 100: 3068–3076.

    Article  PubMed  CAS  Google Scholar 

  163. Vrhovac R, Delmer A, Tang R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F. Prognostic significance of the cell cycle inhibitor p27Kipl in chronic B-cell lymphocytic leukemia. Blood 1998; 91: 4694–4700.

    PubMed  CAS  Google Scholar 

  164. Theml H, Love R, Begemann H. Factors in the pathomechanism of chronic lymphocytic leukemia. Annu Rev Med 1977; 28: 131–41.

    Article  PubMed  CAS  Google Scholar 

  165. Reed JC. Molecular biology of chronic lymphocytic leukemia: implications for therapy. Semin Hematol 1998; 35: 3–13.

    PubMed  CAS  Google Scholar 

  166. Schena M, Larsson LG, Gottardi D, et al. Growth-and differentiation-associated expression of bc1–2 in B-chronic lymphocytic leukemia cells. Blood 1992; 79: 2981–2989.

    PubMed  CAS  Google Scholar 

  167. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 1993; 82: 1820–1828.

    PubMed  CAS  Google Scholar 

  168. Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 1996; 10: 456–459.

    PubMed  CAS  Google Scholar 

  169. McConkey DJ, Chandra J, Wright S, et al. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX. J Immunol 1996; 156: 2624–2630.

    PubMed  CAS  Google Scholar 

  170. Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M. Bcl-2, Bax and p53 expression in BCLL in relation to in vitro survival and clinical progression. Int J Cancer 1996; 69: 114–119.

    Article  PubMed  CAS  Google Scholar 

  171. Rechavi G, Katzir N, Brok-Simoni F, et al. A search for boll, bc12, and c-myc oncogene rearrangements in chronic lymphocytic leukemia. Leukemia 1989; 3: 57–60.

    PubMed  CAS  Google Scholar 

  172. Medeiros LI, Van Krieken JH, Jaffe ES, Raffeld M. Association of bc1–1 rearrangements with lymphocytic lymphoma of intermediate differentiation. Blood 1990; 76: 2086–2090.

    PubMed  CAS  Google Scholar 

  173. Dyer MJ, Zani VJ, Lu WZ, et al. BCL2 translocations in leukemias of mature B cells. Blood 1994; 83: 3682–3688.

    PubMed  CAS  Google Scholar 

  174. Adachi M, Tsujimoto Y. Juxtaposition of human bcl-2 and immunoglobulin lambda light chain gene in chronic lymphocytic leukemia is the result of a reciprocal chromosome translocation between chromosome 18 and 22. Oncogene 1989; 4: 1073–1075.

    PubMed  CAS  Google Scholar 

  175. Tashiro S, Takechi M, Asou H, et al. Cytogenetic 2;18 and 18;22 translocation in chronic lymphocytic leukemia with juxtaposition of bcl-2 and immunoglobulin light chain genes. Oncogene 1992; 7: 573–577.

    PubMed  CAS  Google Scholar 

  176. Laytragoon-Lewin N, Kashuba V, Mellstedt H, Klein G. bcl-2 rearrangement detected by pulsed-field gel electrophoresis (PFGF) in B-chronic lymphocytic leukemia (CLL) cells. Int J Cancer 1998; 76: 909–912.

    Article  PubMed  CAS  Google Scholar 

  177. Gottardi D, Alfarano A, De Leo AM, et al. In leukaemic CD5+ B cells the expression of BCL-2 gene family is shifted toward protection from apoptosis. Br J Haematol 1996; 94: 612–618.

    Article  PubMed  CAS  Google Scholar 

  178. Kitada S, Andersen J, Akar S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood 1998; 91: 3379–3389.

    PubMed  CAS  Google Scholar 

  179. Kitada S, Zapata JM, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 2000; 96: 393–397.

    PubMed  CAS  Google Scholar 

  180. Pepper C, Bentley P, Hoy T. Regulation of clinical chemoresistance by bc1–2 and bax oncoproteins in B-cell chronic lymphocytic leukaemia. Br J Haematol 1996; 95: 513–517.

    Article  PubMed  CAS  Google Scholar 

  181. Molica S, Dattilo A, Giulino C, Levato D, Levato L. Increased bcl-2/bax ratio in B-cell chronic lymphocytic leukemia is associated with a progressive pattern of disease. Haematologica 1998; 83: 1122–1124.

    PubMed  CAS  Google Scholar 

  182. King D, Pringle JH, Hutchinson M, Cohen GM. Processing/activation of caspases, -3 and -7 and -8 but not caspase2, in the induction of apoptosis in B-chronic lymphocytic leukemia cells. Leukemia 1998; 12: 1553–1560.

    Article  PubMed  CAS  Google Scholar 

  183. Panayiotidis P, Jones D, Ganeshaguru K, Foroni L, Hoffbrand AV. Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol 1996; 92: 97–103.

    Article  PubMed  CAS  Google Scholar 

  184. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998; 91: 2387–2396.

    PubMed  CAS  Google Scholar 

  185. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell’ Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 2000; 96: 2655–2663.

    PubMed  CAS  Google Scholar 

  186. Pedersen IM, Kitada S, Leoni LM, et al. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-l. Blood 2002; 100: 1795–1801.

    Article  PubMed  CAS  Google Scholar 

  187. Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bc1–2 expression. J Exp Med 1992; 176: 1319–1326.

    Article  PubMed  CAS  Google Scholar 

  188. Konig A, Menzel T, Lynen S, et al. Basic fibroblast growth factor (bFGF) upregulates the expression of bc1–2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia 1997; 11: 258–265.

    Article  PubMed  CAS  Google Scholar 

  189. Tangye SG, Raison RL. Human cytokines suppress apoptosis of leukaemic CD5+ B cells and preserve expression of bc1–2. Immunol Cell Biol 1997; 75: 127–135.

    Article  PubMed  CAS  Google Scholar 

  190. Bairey O, Zimra Y, Shaklai M, Rabizadeh E. Bc1–2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia. Br J Haematol 2001; 113: 400–406.

    Article  PubMed  CAS  Google Scholar 

  191. Frankfurt OS, Byrnes JJ, Villa L. Protection from apoptotic cell death by interleukin-4 is increased in previously treated chronic lymphocytic leukemia patients. Leuk Res 1997; 21: 9–16.

    Article  PubMed  CAS  Google Scholar 

  192. Thomas A, El Rouby S, Reed JC, et al. Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance. Oncogene 1996; 12: 1055–1062.

    PubMed  CAS  Google Scholar 

  193. Pepper C, Hoy T, Bentley DP. Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance. Br J Cancer 1997; 76: 935–938.

    Article  PubMed  CAS  Google Scholar 

  194. Pepper C, Thomas A, Hidalgo de Quintana J, Davies S, Hoy T, Bentley P. Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia—the role of Bcl-2 family dysregulation. Leuk Res 1999; 23: 1007–1014.

    Article  PubMed  CAS  Google Scholar 

  195. Gottardi D, De Leo AM, Alfarano A, et al. Fludarabine ability to down-regulate Bc1–2 gene product in CD5+ leukaemic B cells: in vitro/in vivo correlations. Br J Haematol 1997; 99: 147–157.

    Article  PubMed  CAS  Google Scholar 

  196. Bromidge TJ, Turner DL, Howe DJ, Johnson SA, Rule SA. In vitro chemosensitivity of chronic lymphocytic leukaemia to purine analogues—correlation with clinical course. Leukemia 1998; 12: 1230–1235.

    Article  PubMed  CAS  Google Scholar 

  197. Consoli U, El-Tounsi I, Sandoval A, et al. Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia. Blood 1998; 91: 1742–1748.

    PubMed  CAS  Google Scholar 

  198. Zaja F, Di Loreto C, Amoroso V, et al. BCL-2 immunohistochemical evaluation in B-cell chronic lymphocytic leukemia and hairy cell leukemia before treatment with fludarabine and 2-chloro-deoxy-adenosine. Leuk Lymphoma 1998; 28: 567–572.

    PubMed  CAS  Google Scholar 

  199. Faderl S, Keating MJ, Do KA, et al. Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia 2002; 16: 1045–1052.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. William G. Wierda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Section of Hematology/Oncology, Veterans Affairs Medical Center, Augusta, GA, USA

    Guy B. Faguet MD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Wierda, W.G. (2004). Molecular Biology of Chronic Lymphocytic Leukemia. In: Faguet, G.B. (eds) Chronic Lymphocytic Leukemia. Contemporary Hematology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-412-2_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-412-2_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-355-8

  • Online ISBN: 978-1-59259-412-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation