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Pathophysiology and genetic features of chronic lymphocytic leukemia

Authors
Kanti R Rai, MD
Stephan Stilgenbauer, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Rebecca F Connor, MD

INTRODUCTION

Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). According to the current WHO classification, B cell CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL) [1]. It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.

The pathophysiology and molecular biology of B cell CLL/SLL will be reviewed here. The incidence, epidemiology, clinical manifestations, diagnosis, and treatment of CLL/SLL and its variants (T cell CLL, prolymphocytic leukemia), and the role of hematopoietic cell transplantation are discussed separately. (See "Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia" and "Hematopoietic cell transplantation in chronic lymphocytic leukemia" and "Clinical manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma".)

OVERVIEW OF PATHOGENESIS

The molecular pathogenesis of chronic lymphocytic leukemia (CLL) is a complex, multistep process leading to the replication of a malignant clone of B-lymphocytes (figure 1). While some steps in this pathway have been elucidated, many remain unknown. It is believed that virtually all CLL cases are preceded by a premalignant B cell proliferative disorder known as monoclonal B cell lymphocytosis (MBL). MBL with a CLL-phenotype is present in 5 to 15 percent of the population above the age of 60 and progresses to CLL/SLL or a related malignancy at a rate of approximately 1 percent per year [2,3]. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Monoclonal B cell lymphocytosis'.)

The pathogenesis of CLL can be conceptualized as two sequential processes:

Establishment of MBL – While the inciting event is unknown, MBL appears to develop as the result of multiple factors, such as response to antigenic stimulation, microenvironmental support, gene mutations, epigenetic modification, and cytogenetic abnormalities. The result is a clone of B cells with a CLL phenotype.

                      

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Literature review current through: Nov 2016. | This topic last updated: Wed May 04 00:00:00 GMT+00:00 2016.
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References
Top
  1. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  2. Rossi D, Sozzi E, Puma A, et al. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors. Br J Haematol 2009; 146:64.
  3. Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol 2009; 27:3959.
  4. Ghia P, Caligaris-Cappio F. Monoclonal B-cell lymphocytosis: right track or red herring? Blood 2012; 119:4358.
  5. Dühren-von Minden M, Übelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012; 489:309.
  6. Wu CJ. CLL clonal heterogeneity: an ecology of competing subpopulations. Blood 2012; 120:4117.
  7. Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 2014; 123:2139.
  8. Puente XS, Beà S, Valdés-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 2015; 526:519.
  9. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature 2015; 526:525.
  10. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 2016; 127:2122.
  11. Pallasch CP, Schulz A, Kutsch N, et al. Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease. Blood 2008; 112:4213.
  12. Messmer BT, Messmer D, Allen SL, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 2005; 115:755.
  13. 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.
  14. Damle RN, Ghiotto F, Valetto A, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 2002; 99:4087.
  15. Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004; 103:4389.
  16. Seifert M, Sellmann L, Bloehdorn J, et al. Cellular origin and pathophysiology of chronic lymphocytic leukemia. J Exp Med 2012; 209:2183.
  17. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990.
  18. Hallek M, Cheson BD, Catovsky D, et al. 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; 111:5446.
  19. Potter KN, Mockridge CI, Neville L, et al. Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia. Clin Cancer Res 2006; 12:1672.
  20. 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.
  21. Fournier S, Delespesse G, Rubio M, et al. CD23 antigen regulation and signaling in chronic lymphocytic leukemia. J Clin Invest 1992; 89:1312.
  22. Boumsell L, Coppin H, Pham D, et al. An antigen shared by a human T cell subset and B cell chronic lymphocytic leukemic cells. Distribution on normal and malignant lymphoid cells. J Exp Med 1980; 152:229.
  23. Freedman AS, Boyd AW, Bieber FR, et al. Normal cellular counterparts of B cell chronic lymphocytic leukemia. Blood 1987; 70:418.
  24. Freedman AS. Immunobiology of chronic lymphocytic leukemia. Hematol Oncol Clin North Am 1990; 4:405.
  25. Kurec AS, Threatte GA, Gottlieb AJ, et al. Immunophenotypic subclassification of chronic lymphocytic leukaemia (CLL). Br J Haematol 1992; 81:45.
  26. Royston I, Majda JA, Baird SM, et al. Human T cell antigens defined by monoclonal antibodies: the 65,000-dalton antigen of T cells (T65) is also found on chronic lymphocytic leukemia cells bearing surface immunoglobulin. J Immunol 1980; 125:725.
  27. Hanson CA, Gribbin TE, Schnitzer B, et al. CD11c (LEU-M5) expression characterizes a B-cell chronic lymphoproliferative disorder with features of both chronic lymphocytic leukemia and hairy cell leukemia. Blood 1990; 76:2360.
  28. Wormsley SB, Baird SM, Gadol N, et al. Characteristics of CD11c+CD5+ chronic B-cell leukemias and the identification of novel peripheral blood B-cell subsets with chronic lymphoid leukemia immunophenotypes. Blood 1990; 76:123.
  29. Antin JH, Emerson SG, Martin P, et al. Leu-1+ (CD5+) B cells. A major lymphoid subpopulation in human fetal spleen: phenotypic and functional studies. J Immunol 1986; 136:505.
  30. Bofill M, Janossy G, Janossa M, et al. Human B cell development. II. Subpopulations in the human fetus. J Immunol 1985; 134:1531.
  31. Caligaris-Cappio F, Gobbi M, Bofill M, Janossy G. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia. J Exp Med 1982; 155:623.
  32. Rawstron AC, Green MJ, Kuzmicki A, 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.
  33. Ghia P, Prato G, Scielzo C, et al. Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood 2004; 103:2337.
  34. Gadol N, Ault KA. Phenotypic and functional characterization of human Leu1 (CD5) B cells. Immunol Rev 1986; 93:23.
  35. Plater-Zyberk C, Maini RN, Lam K, et al. A rheumatoid arthritis B cell subset expresses a phenotype similar to that in chronic lymphocytic leukemia. Arthritis Rheum 1985; 28:971.
  36. Kipps TJ, Tomhave E, Chen PP, Carson DA. Autoantibody-associated kappa light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation. Implications for etiology and immunotherapy. J Exp Med 1988; 167:840.
  37. Kipps TJ, Tomhave E, Pratt LF, et al. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 1989; 86:5913.
  38. Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood 1993; 81:2475.
  39. Inghirami G, Foitl DR, Sabichi A, et al. Autoantibody-associated cross-reactive idiotype-bearing human B lymphocytes: distribution and characterization, including Ig VH gene and CD5 antigen expression. Blood 1991; 78:1503.
  40. Dighiero G. Biology of the neoplastic lymphocyte in B-CLL. Baillieres Clin Haematol 1993; 6:807.
  41. Abe M, Tominaga K, Wakasa H. Phenotypic characterization of human B-lymphocyte subpopulations, particularly human CD5+ B-lymphocyte subpopulation within the mantle zones of secondary follicles. Leukemia 1994; 8:1039.
  42. Lin K, Manocha S, Harris RJ, et al. High frequency of p53 dysfunction and low level of VH mutation in chronic lymphocytic leukemia patients using the VH3-21 gene segment. Blood 2003; 102:1145.
  43. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002; 99:2262.
  44. Tobin G, Thunberg U, Johnson A, et al. Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood 2003; 101:4952.
  45. Ghiotto F, Fais F, Valetto A, et al. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest 2004; 113:1008.
  46. Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012; 119:4467.
  47. Stamatopoulos K, Belessi C, Moreno C, et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. Blood 2007; 109:259.
  48. Thorsélius M, Kröber A, Murray F, et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood 2006; 107:2889.
  49. Athanasiadou A, Stamatopoulos K, Gaitatzi M, et al. Recurrent cytogenetic findings in subsets of patients with chronic lymphocytic leukemia expressing IgG-switched stereotyped immunoglobulins. Haematologica 2008; 93:473.
  50. Strefford JC, Sutton LA, Baliakas P, et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 2013; 27:2196.
  51. Rossi D, Spina V, Bomben R, et al. Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. Blood 2013; 121:4902.
  52. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood 2012; 120:1175.
  53. Dianzani U, Omedè P, Marmont F, et al. Expansion of T cells expressing low CD4 or CD8 levels in B-cell chronic lymphocytic leukemia: correlation with disease status and neoplastic phenotype. Blood 1994; 83:2198.
  54. Scrivener S, Kaminski ER, Demaine A, Prentice AG. Analysis of the expression of critical activation/interaction markers on peripheral blood T cells in B-cell chronic lymphocytic leukaemia: evidence of immune dysregulation. Br J Haematol 2001; 112:959.
  55. Christopoulos P, Pfeifer D, Bartholomé K, et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood 2011; 117:3836.
  56. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013; 121:1612.
  57. Görgün G, Holderried TA, Zahrieh D, et al. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest 2005; 115:1797.
  58. Dighiero G. An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL. Nouv Rev Fr Hematol 1988; 30:283.
  59. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998; 25:80.
  60. Majumdar G, Brown S, Slater NG, Singh AK. Clinical spectrum of autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Leuk Lymphoma 1993; 9:149.
  61. Sthoeger ZM, Sthoeger D, Shtalrid M, et al. Mechanism of autoimmune hemolytic anemia in chronic lymphocytic leukemia. Am J Hematol 1993; 43:259.
  62. Sinisalo M, Aittoniemi J, Oivanen P, et al. Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia. Br J Haematol 2001; 114:107.
  63. Molica S. Infections in chronic lymphocytic leukemia: risk factors, and impact on survival, and treatment. Leuk Lymphoma 1994; 13:203.
  64. Salonen J, Nikoskelainen J. Lethal infections in patients with hematological malignancies. Eur J Haematol 1993; 51:102.
  65. Sampalo A, Navas G, Medina F, et al. Chronic lymphocytic leukemia B cells inhibit spontaneous Ig production by autologous bone marrow cells: role of CD95-CD95L interaction. Blood 2000; 96:3168.
  66. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343:1910.
  67. Reddy KS. Chronic lymphocytic leukaemia profiled for prognosis using a fluorescence in situ hybridisation panel. Br J Haematol 2006; 132:705.
  68. Grubor V, Krasnitz A, Troge JE, et al. Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA). Blood 2009; 113:1294.
  69. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475:101.
  70. Knuutila S, Elonen E, Teerenhovi L, et al. Trisomy 12 in B cells of patients with B-cell chronic lymphocytic leukemia. N Engl J Med 1986; 314:865.
  71. Fegan C, Robinson H, Thompson P, et al. Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of 11q and advanced or progressive disease. Leukemia 1995; 9:2003.
  72. Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol 2006; 24:4634.
  73. Guièze R, Robbe P, Clifford R, et al. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL. Blood 2015; 126:2110.
  74. Döhner 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.
  75. 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.
  76. 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 U S A 1991; 88:5413.
  77. 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.
  78. Cordone I, Masi S, Mauro FR, et al. p53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis. Blood 1998; 91:4342.
  79. Barnabas N, Shurafa M, Van Dyke DL, et al. Significance of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients. Cancer 2001; 91:285.
  80. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365:2497.
  81. Kastan MB, Onyekwere O, Sidransky D, et al. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51:6304.
  82. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A 1992; 89:7491.
  83. Woods DB, Vousden KH. Regulation of p53 function. Exp Cell Res 2001; 264:56.
  84. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014; 123:3247.
  85. Döhner H, Stilgenbauer S, James MR, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997; 89:2516.
  86. Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood 2013; 121:4036.
  87. Khanna KK, Keating KE, Kozlov S, et al. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet 1998; 20:398.
  88. Lehmann S, Ogawa S, Raynaud SD, et al. Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer 2008; 112:1296.
  89. Corcoran MM, Rasool O, Liu Y, et al. Detailed molecular delineation of 13q14.3 loss in B-cell chronic lymphocytic leukemia. Blood 1998; 91:1382.
  90. Kalachikov S, Migliazza A, Cayanis E, et al. Cloning and gene mapping of the chromosome 13q14 region deleted in chronic lymphocytic leukemia. Genomics 1997; 42:369.
  91. Migliazza A, Bosch F, Komatsu H, et al. Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia. Blood 2001; 97:2098.
  92. Garg R, Wierda W, Ferrajoli A, et al. The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. Cancer 2012; 118:3531.
  93. Garcìa-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.
  94. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013; 121:1403.
  95. Hanada M, Delia D, Aiello A, et al. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 1993; 82:1820.
  96. Papakonstantinou G, Verbeke C, Hastka J, et al. bcl-2 expression in non-Hodgkin's lymphomas is not associated with bcl-2 gene rearrangements. Br J Haematol 2001; 113:383.
  97. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117:563.
  98. Hockenbery D, Nuñez G, Milliman C, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348:334.
  99. Galton DA. The pathogenesis of chronic lymphocytic leukemia. Can Med Assoc J 1966; 94:1005.
  100. Dameshek W. Chronic lymphocytic leukemia--an accumulative disease of immunolgically incompetent lymphocytes. Blood 1967; 29:Suppl:566.
  101. Ricciardi MR, Petrucci MT, Gregorj C, et al. Reduced susceptibility to apoptosis correlates with kinetic quiescence in disease progression of chronic lymphocytic leukaemia. Br J Haematol 2001; 113:391.
  102. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208:1389.
  103. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood 2012; 119:329.
  104. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012; 119:521.
  105. Oscier DG, Rose-Zerilli MJ, Winkelmann N, et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 2013; 121:468.
  106. Lionetti M, Fabris S, Cutrona G, et al. High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications. Br J Haematol 2014; 165:629.
  107. Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118:6904.
  108. Hahn CN, Scott HS. Spliceosome mutations in hematopoietic malignancies. Nat Genet 2011; 44:9.
  109. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2011; 44:47.
  110. Mori J, Takahashi Y, Tanimoto T. SF3B1 in chronic lymphocytic leukemia. N Engl J Med 2012; 366:1057; author reply 1057.
  111. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014; 370:2286.
  112. Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 2014; 370:2352.
  113. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol 2015; 1:80.
  114. Lawrie CH. MicroRNAs and haematology: small molecules, big function. Br J Haematol 2007; 137:503.
  115. Calin GA, Croce CM. Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes. Blood 2009; 114:4761.
  116. Visone R, Rassenti LZ, Veronese A, et al. Karyotype-specific microRNA signature in chronic lymphocytic leukemia. Blood 2009; 114:3872.
  117. Calin GA, Croce CM. Genomics of chronic lymphocytic leukemia microRNAs as new players with clinical significance. Semin Oncol 2006; 33:167.
  118. Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353:1793.
  119. Calin GA, Liu CG, Sevignani C, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci U S A 2004; 101:11755.
  120. Fulci V, Chiaretti S, Goldoni M, et al. Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 2007; 109:4944.
  121. Ferrajoli A, Shanafelt TD, Ivan C, et al. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. Blood 2013; 122:1891.
  122. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002; 99:15524.
  123. Mraz M, Chen L, Rassenti LZ, et al. miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood 2014; 124:84.
  124. Corney DC, Flesken-Nikitin A, Godwin AK, et al. MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res 2007; 67:8433.
  125. Sampath D, Liu C, Vasan K, et al. Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 2012; 119:1162.
  126. Fabbri M, Bottoni A, Shimizu M, et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 2011; 305:59.