Seminars in Hematology
Volume 41, Issue 3 , Pages 192-200 , July 2004

Clonal lymphocytes in persons without known chronic lymphocytic leukemia (CLL): implications of recent findings in family members of CLL patients

  • Andy Rawstron

      Affiliations

    • HMDS, Leeds Teaching Hospitals, Leeds, UK
    • Corresponding Author InformationAddress correspondence to Andy Rawstron, PhD, Principal Clinical Scientist, Haematological Malignancy Diagnostic Service, Algernon Firth Building, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK
    • ,
  • Peter Hillmen

      Affiliations

    • HMDS, Leeds Teaching Hospitals, Leeds, UK
    • ,
  • Richard Houlston

      Affiliations

    • Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK

References 

  1. Stilgenbauer S, Bullinger L, Lichter P, Dohner H. Genetics of chronic lymphocytic leukemia (Genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course). Leukemia. 2002;16:993–1007
  2. Stilgenbauer S, Lichter P, Dohner H. Genetic features of B-cell chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2000;4:48–72
  3. Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, et al.  V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410–1416
  4. Dohner H, Stilgenbauer S, Fischer K, Bentz M, Lichter P. Cytogenetic and molecular cytogenetic analysis of B cell chronic lymphocytic leukemia (Specific chromosome aberrations identify prognostic subgroups of patients and point to loci of candidate genes). Leukemia. 1997;11(suppl 2):S19–S24
  5. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al.  Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–1916
  6. Chevallier P, Penther D, Avet-Loiseau H, Robillard N, Ifrah N, Mahe B, et al.  CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukaemia. Br J Haematol. 2002;116:142–150
  7. Bea S, Lopez-Guillermo A, Ribas M, Puig X, Pinyol M, Carrio A, et al.  Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter’s syndrome). Am J Pathol. 2002;161:957–968
  8. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–1854
  9. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al.  Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840–1847
  10. Rajewsky K. Clonal selection and learning in the antibody system. Nature. 1996;381:751–758
  11. Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ, et al.  B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood. 2002;99:4087–4093
  12. Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, et al.  Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194:1625–1638
  13. 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
  14. 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
  15. Lagneaux L, Delforge A, De Bruyn C, Bernier M, Bron D. Adhesion to bone marrow stroma inhibits apoptosis of chronic lymphocytic leukemia cells. Leuk Lymphoma. 1999;35:445–453
  16. Granziero L, Circosta P, Scielzo C, Frisaldi E, Stella S, Geuna M, et al.  CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood. 2003;101:1962–1969
  17. 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
  18. Tsukada N, Burger JA, Zvaifler NJ, Kipps TJ. Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia. Blood. 2002;99:1030–1037
  19. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER∗Stat Database: Mortality-All COD, Public-Use With State, Total U.S. (1969-2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003. Underlying mortality data provided by NCHS (www.cdc.gov/nchs)
  20. Goldman JM, Melo JV. Chronic myeloid leukemia—Advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464
  21. Yuille MR, Matutes E, Marossy A, Hilditch B, Catovsky D, Houlston RS. Familial chronic lymphocytic leukaemia (A survey and review of published studies). Br J Haematol. 2000;109:794–799
  22. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, et al.  A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306:234–238
  23. Mueller CR, Roskelley CD. Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res. 2003;5:45–52
  24. Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, et al.  Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet. 1999;21:236–240
  25. Lambie H, Miremadi A, Pinder SE, Bell JA, Wencyk P, Paish EC, et al.  Prognostic significance of BRCA1 expression in sporadic breast carcinomas. J Pathol. 2003;200:207–213
  26. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001;1:55–67
  27. Gunz FW, Gunz JP, Veale AM, Chapman CJ, Houston IB. Familial leukaemia (A study of 909 families). Scand J Haematol. 1975;15:117–131
  28. Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM, Panton J. Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972–80 (Occupational and familial aspects). J Natl Cancer Inst. 1984;72:1233–1240
  29. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994;86:1600–1608
  30. Cartwright RA, Bernard SM, Bird CC, Darwin CM, O’Brien C, Richards ID, et al.  Chronic lymphocytic leukaemia (case control epidemiological study in Yorkshire). Br J Cancer. 1987;56:79–82
  31. Linet MS, Van Natta ML, Brookmeyer R, Khoury MJ, McCaffrey LD, Humphrey RL, et al.  Familial cancer history and chronic lymphocytic leukemia. A case-control study. Am J Epidemiol. 1989;130:655–664
  32. Pottern LM, Linet M, Blair A, Dick F, Burmeister LF, Gibson R, et al.  Familial cancers associated with subtypes of leukemia and non-Hodgkin’s lymphoma. Leuk Res. 1991;15:305–314
  33. Goldin LR, Pfeiffer RM, Li X, Heminki K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukaemia (Results from the Swedish Family-Cancer Database). Blood. 2004; May, 10.1182/blood-2004-01-0341 (epub)
  34. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–1517
  35. Houlston RS, Peto J. The future of association studies of common cancers. Hum Genet. 2003;112:434–435
  36. Binet JL, Lepoprier M, Dighiero G, Charron D, D’Athis P, Vaugier G, et al.  A clinical staging system for chronic lymphocytic leukemia (Prognostic significance). Cancer. 1977;40:855–864
  37. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–234
  38. Thomas R, Ribeiro I, Shepherd P, Johnson P, Cook M, Lakhani A, et al.  Spontaneous clinical regression in chronic lymphocytic leukaemia. Br J Haematol. 2002;116:341–345
  39. Han T, Ozer H, Gavigan M, Gajera R, Minowada J, Bloom ML, et al.  Benign monoclonal B cell lymphocytosis—A benign variant of CLL (Clinical, immunologic, phenotypic, and cytogenetic studies in 20 patients). Blood. 1984;64:244–252
  40. Batata A, Shen B. Chronic lymphocytic leukemia with low lymphocyte count. Cancer. 1993;71:2732–2738
  41. Bassan R, Buzzetti M, Marini B, Rambaldi A, Allavena P, Barbui T. Investigation of chronic lymphocytosis in adults. Am J Clin Pathol. 1988;89:783–787
  42. Aman P, Mellstedt H. The leukemic B-cell population of patients with monoclonal lymphocytosis of undetermined significance (MLUS) are functionally distinct from the chronic lymphocytic leukemia (CLL) derived cell population. Leuk Res. 1991;15:715–719
  43. Molica S, Levato D. What is changing in the natural history of chronic lymphocytic leukemia?. Haematologica. 2001;86:8–12
  44. LeMaoult J, Szabo P, Weksler ME. Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development. Immunol Rev. 1997;160:115–126
  45. Rawstron AC, Kennedy B, Evans PA, Davies FE, Richards SJ, Haynes AP, et al.  Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood. 2001;98:29–35
  46. Gearhart PJ. Immunology (The roots of antibody diversity). Nature. 2002;419:29–31
  47. Kuppers R. Somatic hypermutation and B cell receptor selection in normal and transformed human B cells. Ann NY Acad Sci. 2003;987:173–179
  48. Bakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K. Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood. 1992;80:2326–2335
  49. Korganow AS, Martin T, Weber JC, Lioure B, Lutz P, Knapp AM, 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
  50. Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, Castle BE, et al.  Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood. 2003;101:3574–3580
  51. McCarthy H, Wierda WG, Barron LL, Cromwell CC, Wang J, Coombes KR, et al.  High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor-prognosis chronic lymphocytic leukemia. Blood. 2003;101:4903–4908
  52. Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzi N. Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells (Expression as multiple forms in a dynamic, variably sized fraction of the clone). Blood. 2003;102:3333–3339
  53. Gurrieri C, McGuire P, Zan H, Yan XJ, Cerutti A, Albesiano E, et al.  Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification. J Exp Med. 2002;196:629–639
  54. Sahota SS, Davis Z, Hamblin TJ, Stevenson FK. Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia. Blood. 2000;95:3534–3540
  55. Sarasua SM, Vogt RF, Middleton DC, Slade BA, McGeehin MA, Lybarger JA. “CLL-Like” B-cell phenotypes detected in superfund studies (Epidemiologic methods and findings). In:  Marti GE,  Vogt RF,  Zenger VE editor. 1995; Proceedings of a USPHS Workshop On Laboratory Approaches to Determining the Role of Environmental Exposures as Risk Factors for B-Cell Chronic Lymphocytic Leukemia and Other B-Cell Lymphoproliferative Disorders. Atlanta, GA, June, http://omrb.pnpi.spb.ru/cytometry/14_leuk/contents.htm
  56. Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE, et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry. 2003;52B:1–12
  57. Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, et al.  Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002;100:635–639
  58. Ghia P, Prato G, Scielzo C, Stella S, Geuna M, Guida G, et al.  Monoclonal CD5+ and CD5− B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood. 2004;103:2337–2342
  59. Dolken G, Illerhaus G, Hirt C, Mertelsmann R. BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases. J Clin Oncol. 1996;14:1333–1344
  60. Ji W, Qu GZ, Ye P, Zhang XY, Halabi S, Ehrlich M. Frequent detection of bcl-2/JH translocations in human blood and organ samples by a quantitative polymerase chain reaction assay. Cancer Res. 1995;55:2876–2882
  61. Limpens J, Stad R, Vos C, de Vlaam C, de Jong D, van Ommen GJ, et al.  Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood. 1995;85:2528–2536
  62. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al.  A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–569
  63. Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, et al.  Genetics and cytogenetics of multiple myeloma (A workshop report). Cancer Res. 2004;64:1546–1558
  64. Sahota SS, Leo R, Hamblin TJ, Stevenson FK. Ig VH gene mutational patterns indicate different tumor cell status in human myeloma and monoclonal gammopathy of undetermined significance. Blood. 1996;87:746–755
  65. Ocqueteau M, Orfao A, Almeida J, Blade J, Gonzalez M, Garcia-Sanz R, et al.  Immunophenotypic characterization of plasma cells from monoclonal gammopathy of undetermined significance patients. Implications for the differential diagnosis between MGUS and multiple myeloma. Am J Pathol. 1998;152:1655–1665
  66. Rawstron AC, Fenton JA, Ashcroft J, English A, Jones RA, Richards SJ, et al.  The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells. Blood. 2000;96:3880–3886
  67. O’Connor SJM, Rawstron AC, Plummer M, Hillmen P, Owen RG, Jack AS. Demonstration of the genotypic relationship between CLUS and clinical B-CLL. Leuk Lymphoma. 2003;44(suppl 2):S13; (abstr)
  68. Rawstron AC, de Tute R, O’Connor SJM, Richards SJ, Jack AS, Hillmen P. The natural history of “early CLL.”. Blood. 2003;102(suppl A):188a; (abstr)
  69. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE, et al.  ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944–4951
  70. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764–1775
  71. Sakai A, Marti GE, Caporaso N, Pittaluga S, Touchman JW, Fend F, et al.  Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL. Blood. 2000;95:1413–1419
  72. Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ, et al.  Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood. 2002;100:2289–2290
  73. Rawstron AC, de Tute R, Cullen MJ, Yuille M, Kennedy B, Jack AS, et al.  Sub-clinical CLL is found in a high proportion of “normal” relatives from CLL families (Young adults show the highest relative risk). Blood. 2002;100(suppl A):627; (abstr)
  74. Rachel JM, Zucker ML, Plapp FV, Fox CM, Marti GE, Abbasi F, et al.  B cell monoclonal lymphocytosis in blood donors. Blood. 2002;100(suppl A):2321; (abstr)

PII: S0037-1963(04)00088-5

doi: 10.1053/j.seminhematol.2004.05.001

Seminars in Hematology
Volume 41, Issue 3 , Pages 192-200 , July 2004

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