Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2020, 164(4):425-434 | DOI: 10.5507/bp.2019.046

Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study

Kamila Stranskaa,b, Karla Plevovaa,b, Hana Skuhrova Francovaa, Hana Skabrahovaa, Magdalena von Jagwitz-Biegnitza, Lenka Radovab, Anna Panovskaa, Stanislava Hrobkovaa, Yvona Brychtovaa, Renata Urbanovac, Lukas Smolejd, Martin Simkovicd, Jana Zuchnickae, Lekaa Mohammadovaf, Martin Spacekg, Jiri Mayera, Sarka Pospisilovaa,b, Michael Doubeka,b
a Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
b Central European Institute of Technology, Masaryk University, Brno, Czech Republic
c Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic
d 4th Department of Internal Medicine - Hematology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
e Department of Hematooncology, University Hospital Ostrava, Czech Republic
f Department of Hematology and Oncology, University Hospital Pilsen, Czech Republic
g 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

Aims: This is a nation-wide survey of chronic lymphocytic leukemia (CLL) patients at six large hematology centers in the Czech Republic. The aim was to identify specific populations, social, and health characteristics of CLL subgroups divided according to the immunogenetic features of their B cell receptors (BCRs) and clonality.

Patients and Methods: Questionnaires directed to specific health, social, and environmental conditions were collected in a cohort of 573 CLL patients. For these patients, immunoglobulin heavy chain gene rearrangements were also analyzed in order to gain information about their clonality, IGHV mutational status, and the presence of stereotyped BCRs. Data extracted from the questionnaires were analyzed statistically in the context of immunogenetic features of the cohort.

Results: There were no statistically significant differences in the data collected in the survey between patients with mutated and patients with unmutated IGHV. However, patients with oligoclonal CLL reported health conditions such as hypercholesterolemia, hypertension, herpes simplex, tumors, and also, separately, CLL in 1st degree relatives, more often than their monoclonal counterparts. In patients with stereotyped BCRs, we found more frequent alcohol consumption and gastric infections in subset #1 cases and frequent cholecystectomies and familial CLL in subset #2 cases.

Conclusion: To the best of our knowledge, this study is the first to investigate CLL immunogenetic features and clonality in the context of epidemiological data. We reported statistically significant associations suggesting the influence of certain health and social conditions on a number of clonal populations expanding in CLL and also on characteristic BCR features, especially stereotypy.

Keywords: chronic lymphocytic leukemia, B-cell receptor, clonality, questionnaire, patient history, biological risk factor

Received: May 9, 2019; Revised: August 30, 2019; Accepted: September 4, 2019; Prepublished online: September 26, 2019; Published: December 15, 2020  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Stranska, K., Plevova, K., Skuhrova Francova, H., Skabrahova, H., von Jagwitz-Biegnitz, M., Radova, L., ... Doubek, M. (2020). Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study. Biomedical papers164(4), 425-434. doi: 10.5507/bp.2019.046
Download citation

Supplementary files

Download fileBiomed164-4-425-434-Supp.pdf

File size: 1.4 MB

References

  1. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343(26):1910-6. Go to original source... Go to PubMed...
  2. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94(6):1840-7. Go to original source...
  3. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004;351(9):893-901. Go to original source... Go to PubMed...
  4. 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(3):456-9. Go to PubMed...
  5. Ferreira PG, Jares P, Rico D, Gomez-Lopez G, Martinez-Trillos A, Villamor N, Ecker S, Gonzalez-Perez A, Knowles DG, Monlong J, Johnson R, Quesada V, Djebali S, Papasaikas P, Lopez-Guerra M, Colomer D, Royo C, Cazorla M, Pinyol M, Clot G, Aymerich M, Rozman M, Kulis M, Tamborero D, Gouin A, Blanc J, Gut M, Gut I, Puente XS, Pisano DG, Martin-Subero JI, Lopez-Bigas N, Lopez-Guillermo A, Valencia A, Lopez-Otin C, Campo E, Guigo R. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia. Genome Res 2014;24(2):212-26. Go to original source... Go to PubMed...
  6. Oscier DG, Rose-Zerilli MJ, Winkelmann N, de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 2013;121(3):468-75. Go to original source... Go to PubMed...
  7. Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foa R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013;121(8):1403-12. Go to original source... Go to PubMed...
  8. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, Buhler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Dohner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010;28(29):4473-9. Go to original source... Go to PubMed...
  9. Rossi D, Ciardullo C, Spina V, Gaidano G. Molecular bases of chronic lymphocytic leukemia in light of new treatments. Immunol Lett 2013;155(1-2):51-5. Go to original source... Go to PubMed...
  10. Guieze R, Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 2015;126(4):445-53. Go to original source... Go to PubMed...
  11. Balatti V, Pekarky Y, Croce CM. Role of microRNA in chronic lymphocytic leukemia onset and progression. J Hematol Oncol 2015;8:12. Go to original source... Go to PubMed...
  12. Baliakas P, Hadzidimitriou A, Sutton LA, Minga E, Agathangelidis A, Nichelatti M, Tsanousa A, Scarfo L, Davis Z, Yan XJ, Shanafelt T, Plevova K, Sandberg Y, Vojdeman FJ, Boudjogra M, Tzenou T, Chatzouli M, Chu CC, Veronese S, Gardiner A, Mansouri L, Smedby KE, Pedersen LB, van Lom K, Giudicelli V, Francova HS, Nguyen-Khac F, Panagiotidis P, Juliusson G, Angelis L, Anagnostopoulos A, Lefranc MP, Facco M, Trentin L, Catherwood M, Montillo M, Geisler CH, Langerak AW, Pospisilova S, Chiorazzi N, Oscier D, Jelinek DF, Darzentas N, Belessi C, Davi F, Rosenquist R, Ghia P, Stamatopoulos K. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study. Lancet Haematol 2014;1(2):e74-84. Go to original source... Go to PubMed...
  13. 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(6):1848-54. Go to original source...
  14. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011;117(2):563-74. Go to original source... Go to PubMed...
  15. Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment. Biochim Biophys Acta 2016;1863(3):401-13. Go to original source... Go to PubMed...
  16. Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan XJ, Davis Z, van Gastel-Mol EJ, Tresoldi C, Chu CC, Cahill N, Giudicelli V, Tichy B, Pedersen LB, Foroni L, Bonello L, Janus A, Smedby K, Anagnostopoulos A, Merle-Beral H, Laoutaris N, Juliusson G, di Celle PF, Pospisilova S, Jurlander J, Geisler C, Tsaftaris A, Lefranc MP, Langerak AW, Oscier DG, Chiorazzi N, Belessi C, Davi F, Rosenquist R, Ghia P, Stamatopoulos K. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012;119(19):4467-75. Go to original source... Go to PubMed...
  17. Catera R, Silverman GJ, Hatzi K, Seiler T, Didier S, Zhang L, Herve M, Meffre E, Oscier DG, Vlassara H, Scofield RH, Chen Y, Allen SL, Kolitz J, Rai KR, Chu CC, Chiorazzi N. Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation. Mol Med 2008;14(11-12):665-74. Go to original source... Go to PubMed...
  18. Chu CC, Catera R, Zhang L, Didier S, Agagnina BM, Damle RN, Kaufman MS, Kolitz JE, Allen SL, Rai KR, Chiorazzi N. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 2010;115(19):3907-15. Go to original source... Go to PubMed...
  19. Lanemo Myhrinder A, Hellqvist E, Sidorova E, Soderberg A, Baxendale H, Dahle C, Willander K, Tobin G, Backman E, Soderberg O, Rosenquist R, Horkko S, Rosen A. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood 2008;111(7):3838-48. Go to original source... Go to PubMed...
  20. Binder M, Lechenne B, Ummanni R, Scharf C, Balabanov S, Trusch M, Schluter H, Braren I, Spillner E, Trepel M. Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. PLoS One 2010;5(12):e15992. Go to original source... Go to PubMed...
  21. ten Hacken E, Gounari M, Back JW, Shimanovskaya E, Scarfo L, Kim E, Burks J, Ponzoni M, Ramirez GA, Wierda WG, Estrov Z, Keating MJ, Ferrajoli A, Stamatopoulos K, Ghia P, Burger JA. Calreticulin as a novel B-cell receptor antigen in chronic lymphocytic leukemia. Haematologica 2017;102(10):e394-6. Go to original source... Go to PubMed...
  22. Catera R, Liu Y, Gao C, Yan XJ, Magli A, Allen SL, Kolitz JE, Rai KR, Chu CC, Feizi T, Stamatopoulos K, Chiorazzi N. Binding of CLL subset 4 B-cell receptor immunoglobulins to viable human memory B lymphocytes requires a distinctive IGKV somatic mutation. Mol Med 2017;23:1-12. Go to original source... Go to PubMed...
  23. Hoogeboom R, van Kessel KP, Hochstenbach F, Wormhoudt TA, Reinten RJ, Wagner K, Kater AP, Guikema JE, Bende RJ, van Noesel CJ. A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J Exp Med 2013;210(1):59-70. Go to original source... Go to PubMed...
  24. Hwang KK, Trama AM, Kozink DM, Chen X, Wiehe K, Cooper AJ, Xia SM, Wang M, Marshall DJ, Whitesides J, Alam M, Tomaras GD, Allen SL, Rai KR, McKeating J, Catera R, Yan XJ, Chu CC, Kelsoe G, Liao HX, Chiorazzi N, Haynes BF. IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria. PLoS One 2014;9(3):e90725. Go to original source... Go to PubMed...
  25. Que X, Widhopf G. F. 2nd, Amir S, Hartvigsen K, Hansen LF, Woelkers D, Tsimikas S, Binder CJ, Kipps TJ, Witztum JL. IGHV1-69-encoded antibodies expressed in chronic lymphocytic leukemia react with malondialdehyde-acetaldehyde adduct, an immunodominant oxidation-specific epitope. PLoS One 2013;8(6):e65203. Go to original source... Go to PubMed...
  26. Steininger C, Widhopf G. F. 2nd, Ghia EM, Morello CS, Vanura K, Sanders R, Spector D, Guiney D, Jager U, Kipps TJ. Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. Blood 2012;119(10):2293-301. Go to original source... Go to PubMed...
  27. Duhren-von Minden M, Ubelhart R, Schneider D, Wossning T, Bach MP, Buchner M, Hofmann D, Surova E, Follo M, Kohler F, Wardemann H, Zirlik K, Veelken H, Jumaa H. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012;489(7415):309-12. Go to original source... Go to PubMed...
  28. Minici C, Gounari M, Ubelhart R, Scarfo L, Duhren-von Minden M, Schneider D, Tasdogan A, Alkhatib A, Agathangelidis A, Ntoufa S, Chiorazzi N, Jumaa H, Stamatopoulos K, Ghia P, Degano M. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nat Commun 2017;8:15746. Go to original source... Go to PubMed...
  29. Herve M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, Meffre E. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest 2005;115(6):1636-43. Go to original source... Go to PubMed...
  30. Seiler T, Woelfle M, Yancopoulos S, Catera R, Li W, Hatzi K, Moreno C, Torres M, Paul S, Dohner H, Stilgenbauer S, Kaufman MS, Kolitz JE, Allen SL, Rai KR, Chu CC, Chiorazzi N. Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells. Blood 2009;114(17):3615-24. Go to original source... Go to PubMed...
  31. Brazdilova K, Plevova K, Skuhrova Francova H, Kockova H, Borsky M, Bikos V, Malcikova J, Oltova A, Kotaskova J, Tichy B, Brychtova Y, Mayer J, Doubek M, Pospisilova S. Multiple productive IGH rearrangements denote oligoclonality even in immunophenotypically monoclonal CLL. Leukemia 2018;32(1):234-6. Go to original source... Go to PubMed...
  32. Plevova K, Francova HS, Burckova K, Brychtova Y, Doubek M, Pavlova S, Malcikova J, Mayer J, Tichy B, Pospisilova S. Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones. Haematologica 2014;99(2):329-38. Go to original source... Go to PubMed...
  33. Stamatopoulos B, Timbs A, Bruce D, Smith T, Clifford R, Robbe P, Burns A, Vavoulis D V, Lopez L, Antoniou P, Mason J, Dreau H, Schuh A. Targeted deep sequencing reveals clinically relevant subclonal IgHV rearrangements in chronic lymphocytic leukemia. Leukemia 2017;31(4):837-45. Go to original source... Go to PubMed...
  34. Anderson LA, Landgren O, Engels EA. Common community acquired infections and subsequent risk of chronic lymphocytic leukaemia. Br J Haematol 2009;147(4):444-9. Go to original source... Go to PubMed...
  35. Landgren O, Gridley G, Check D, Caporaso NE, Morris Brown L. Acquired immune-related and inflammatory conditions and subsequent chronic lymphocytic leukaemia. Br J Haematol 2007;139(5):791-8. Go to original source... Go to PubMed...
  36. Landgren O, Rapkin JS, Caporaso NE, Mellemkjaer L, Gridley G, Goldin LR, Engels EA. Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia. Blood 2007;109(5):2198-201. Go to original source... Go to PubMed...
  37. Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, Monnereau A, Nieters A, Clavel J, Call TG, Maynadie M, Lan Q, Clarke CA, Lightfoot T, Norman AD, Sampson JN, Casabonne D, Cocco P, de Sanjose S. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014;2014(48):41-51. Go to original source... Go to PubMed...
  38. Soderberg KC, Jonsson F, Winqvist O, Hagmar L, Feychting M. Autoimmune diseases, asthma and risk of haematological malignancies: a nationwide case-control study in Sweden. Eur J Cancer 2006;42(17):3028-33. Go to original source... Go to PubMed...
  39. Vanura K, Le T, Esterbauer H, Spath F, Porpaczy E, Shehata M, Eigenberger K, Hauswirth A, Skrabs C, Kromer E, Schwarzinger I, Streubel B, Steininger C, Fonatsch C, Stilgenbauer S, Wagner O, Gaiger A, Jager U. Autoimmune conditions and chronic infections in chronic lymphocytic leukemia patients at diagnosis are associated with unmutated IgVH genes. Haematologica 2008;93(12):1912-6. Go to original source... Go to PubMed...
  40. Karakosta M, Delicha EM, Kouraklis G, Manola KN. Association of various risk factors with chronic lymphocytic leukemia and its cytogenetic characteristics. Arch Env Occup Heal 2016;71(6):317-29. Go to original source... Go to PubMed...
  41. Benavente Y, Casabonne D, Costas L, Robles C, Alonso E, de la Banda E, Gonzalez-Barca E, Marcos-Gragera R, Llorca J, Tardon A, Monleon JJ, Aymerich M, Campo E, Gimeno-Vazquez E, Castano-Vinyals G, Aragones N, Pollan M, Kogevinas M, de Sanjose S. Established and suggested exposures on CLL/SLL etiology: Results from the CLL-MCC-Spain study. Cancer Epidemiol 2018;52:106-11. Go to original source... Go to PubMed...
  42. Brown JR, Neuberg D, Phillips K, Reynolds H, Silverstein J, Clark JC, Ash M, Thompson C, Fisher DC, Jacobsen E, LaCasce AS, Freedman AS. Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders. Br J Haematol 2008;143(3):361-8. Go to original source... Go to PubMed...
  43. Goldin LR, Bjorkholm M, Kristinsson SY, Turesson I, Landgren O. Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin's lymphomas among relatives of patients with chronic lymphocytic leukemia. Haematologica 2009;94(5):647-53. Go to original source... Go to PubMed...
  44. Rebora P, Lee M, Czene K, Valsecchi MG, Reilly M. High risks of familial chronic lymphatic leukemia for specific relatives: signposts for genetic discovery? Leukemia 2012;26(11):2419-21. Go to original source... Go to PubMed...
  45. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. 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 2008;111(12):5446-56. Go to original source... Go to PubMed...
  46. Bystry V, Agathangelidis A, Bikos V, Sutton LA, Baliakas P, Hadzidimitriou A, Stamatopoulos K, Darzentas N. ARResT/AssignSubsets: a novel application for robust subclassification of chronic lymphocytic leukemia based on B cell receptor IG stereotypy. Bioinformatics 2015;31(23):3844-6. Go to original source... Go to PubMed...
  47. Malcikova J, Tausch E, Rossi D, Sutton LA, Soussi T, Zenz T, Kater AP, Niemann CU, Gonzalez D, Davi F, Gonzalez Diaz M, Moreno C, Gaidano G, Stamatopoulos K, Rosenquist R, Stilgenbauer S, Ghia P, Pospisilova S. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation. Leukemia 2018;32(5):1070-80. Go to original source... Go to PubMed...
  48. Malcikova J, Stano-Kozubik K, Tichy B, Kantorova B, Pavlova S, Tom N, Radova L, Smardova J, Pardy F, Doubek M, Brychtova Y, Mraz M, Plevova K, Diviskova E, Oltova A, Mayer J, Pospisilova S, Trbusek M. Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia 2015;29(4):877-85. Go to original source... Go to PubMed...
  49. Baliakas P, Iskas M, Gardiner A, Davis Z, Plevova K, Nguyen-Khac F, Malcikova J, Anagnostopoulos A, Glide S, Mould S, Stepanovska K, Brejcha M, Belessi C, Davi F, Pospisilova S, Athanasiadou A, Stamatopoulos K, Oscier D. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. Am J Hematol 2014;89(3):249-55. Go to original source... Go to PubMed...
  50. Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood 2019;133(11):1205-16. Go to original source... Go to PubMed...
  51. Xochelli A, Baliakas P, Kavakiotis I, Agathangelidis A, Sutton LA, Minga E, Ntoufa S, Tausch E, Yan XJ, Shanafelt T, Plevova K, Boudjogra M, Rossi D, Davis Z, Navarro A, Sandberg Y, Vojdeman FJ, Scarfo L, Stavroyianni N, Sudarikov A, Veronese S, Tzenou T, Karan-Djurasevic T, Catherwood M, Kienle D, Chatzouli M, Facco M, Bahlo J, Pott C, Pedersen LB, Mansouri L, Smedby KE, Chu CC, Giudicelli V, Lefranc MP, Panagiotidis P, Juliusson G, Anagnostopoulos A, Vlahavas I, Antic D, Trentin L, Montillo M, Niemann C, Dohner H, Langerak AW, Pospisilova S, Hallek M, Campo E, Chiorazzi N, Maglaveras N, Oscier D, Gaidano G, Jelinek DF, Stilgenbauer S, Chouvarda I, Darzentas N, Belessi C, Davi F, Hadzidimitriou A, Rosenquist R, Ghia P, Stamatopoulos K. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes. Clin Cancer Res 2017;23(17):5292-301. Go to original source... Go to PubMed...
  52. Kostareli E, Gounari M, Agathangelidis A, Stamatopoulos K. Immunoglobulin gene repertoire in chronic lymphocytic leukemia: Insight into antigen selection and microenvironmental interactions. Mediterr J Hematol Infect Dis 2012;4(1):e2012052. Go to original source... Go to PubMed...
  53. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematol Am Soc Hematol Educ Progr 2017;2017(1):329-37. Go to original source... Go to PubMed...
  54. Langerak AW, Davi F, Ghia P, Hadzidimitriou A, Murray F, Potter KN, Rosenquist R, Stamatopoulos K, Belessi C. Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases. Leukemia 2011;25(6):979-84. Go to original source... Go to PubMed...
  55. Visco C, Moretta F, Falisi E, Facco M, Maura F, Novella E, Nichele I, Finotto S, Giaretta I, Ave E, Perbellini O, Guercini N, Scupoli MT, Trentin L, Trimarco V, Neri A, Semenzato G, Rodeghiero F, Pizzolo G, Ambrosetti A. Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia. Am J Hematol 2013;88(4):277-82. Go to original source... Go to PubMed...
  56. Mimmi S, Vecchio E, Iaccino E, Rossi M, Lupia A, Albano F, Chiurazzi F, Fiume G, Pisano A, Ceglia S, Pontoriero M, Golino G, Tassone P, Quinto I, Scala G, Palmieri C. Evidence of shared epitopic reactivity among independent B-cell clones in chronic lymphocytic leukemia patients. Leukemia 2016;30(12):2419-22. Go to original source... Go to PubMed...
  57. Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, Diop M, Scourzic L, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kikushige Y, Davi F, Lambert J, Gautheret D, Merle-Beral H, Sutton L, Dessen P, Solary E, Akashi K, Vainchenker W, Mercher T, Droin N, Ogawa S, Nguyen-Khac F, Bernard OA. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov 2014;4(9):1088-101. Go to original source... Go to PubMed...
  58. Kikushige Y, Ishikawa F, Miyamoto T, Shima T, Urata S, Yoshimoto G, Mori Y, Iino T, Yamauchi T, Eto T, Niiro H, Iwasaki H, Takenaka K, Akashi K. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 2011;20(2):246-59. Go to original source... Go to PubMed...
  59. Mozessohn L, Earle C, Spaner D, Cheng SY, Kumar M, Buckstein R. The Association of Dyslipidemia With Chronic Lymphocytic Leukemia: A Population-Based Study. J Natl Cancer Inst 2017;109(3). Go to original source... Go to PubMed...
  60. Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ, Jack AS, Matutes E, Catovsky D, Hillmen P, Houlston RS. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002;100(7):2289-90. Go to original source... Go to PubMed...
  61. Lanasa MC, Allgood SD, Volkheimer AD, Gockerman JP, Whitesides JF, Goodman BK, Moore JO, Weinberg JB, Levesque MC. Single-cell analysis reveals oligoclonality among "low-count" monoclonal B-cell lymphocytosis. Leukemia 2010;24(1):133-40. Go to original source... Go to PubMed...
  62. Baliakas P, Agathangelidis A, Hadzidimitriou A, Sutton LA, Minga E, Tsanousa A, Scarfo L, Davis Z, Yan XJ, Shanafelt T, Plevova K, Sandberg Y, Vojdeman FJ, Boudjogra M, Tzenou T, Chatzouli M, Chu CC, Veronese S, Gardiner A, Mansouri L, Smedby KE, Pedersen LB, Moreno D, Van Lom K, Giudicelli V, Francova HS, Nguyen-Khac F, Panagiotidis P, Juliusson G, Angelis L, Anagnostopoulos A, Lefranc MP, Facco M, Trentin L, Catherwood M, Montillo M, Geisler CH, Langerak AW, Pospisilova S, Chiorazzi N, Oscier D, Jelinek DF, Darzentas N, Belessi C, Davi F, Ghia P, Rosenquist R, Stamatopoulos K. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations. Blood 2015;125(5):856-9. Go to original source... Go to PubMed...
  63. Mansouri L, Sutton LA, Ljungstrom V, Bondza S, Arngarden L, Bhoi S, Larsson J, Cortese D, Kalushkova A, Plevova K, Young E, Gunnarsson R, Falk-Sorqvist E, Lonn P, Muggen AF, Yan XJ, Sander B, Enblad G, Smedby KE, Juliusson G, Belessi C, Rung J, Chiorazzi N, Strefford JC, Langerak AW, Pospisilova S, Davi F, Hellstrom M, Jernberg-Wiklund H, Ghia P, Soderberg O, Stamatopoulos K, Nilsson M, Rosenquist R. Functional loss of IkappaBepsilon leads to NF-kappaB deregulation in aggressive chronic lymphocytic leukemia. J Exp Med 2015;212(6):833-43. Go to original source... Go to PubMed...
  64. Rossi D, Spina V, Cerri M, Rasi S, Deambrogi C, De Paoli L, Laurenti L, Maffei R, Forconi F, Bertoni F, Zucca E, Agostinelli C, Cabras A, Lucioni M, Martini M, Magni M, Deaglio S, Ladetto M, Nomdedeu JF, Besson C, Ramponi A, Canzonieri V, Paulli M, Marasca R, Larocca LM, Carbone A, Pileri SA, Gattei V, Gaidano G. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res 2009;15(13):4415-22. Go to original source... Go to PubMed...
  65. Sutton LA, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K, Rossi D, Kminkova J, Stalika E, Pedersen LB, Malcikova J, Agathangelidis A, Davis Z, Mansouri L, Scarfo L, Boudjoghra M, Navarro A, Muggen AF, Yan XJ, Nguyen-Khac F, Larrayoz M, Panagiotidis P, Chiorazzi N, Utoft Niemann C, Belessi C, Campo E, Strefford JC, Langerak AW, Oscier D, Gaidano G, Pospisilova S, Davi F, Ghia P, Stamatopoulos K, Rosenquist R. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Haematologica 2016;101(8):959-67. Go to original source... Go to PubMed...
  66. Santambrogio E, Orsucci L. Helicobacter pylori and hematological disorders. Minerva Gastroenterol Dietol 2019 Apr 16. [Epub ahead of print] doi:10.23736/s1121-421x.19.02580-7. Go to original source... Go to PubMed...

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.