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  • Review Article
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The molecular pathogenesis of chronic lymphocytic leukaemia

Key Points

  • Chronic lymphocytic leukaemia (CLL), the most common leukaemia in the Western world, is a heterogeneous disease, comprising two main subtypes (known as immunoglobulin heavy chain variable region-mutated (IGHV-M) and IGHV-unmutated (IGHV-UM) CLLs). These subtypes are historically associated with a good and a poor prognosis, respectively, and differ in underlying genetic lesions, degree of genetic clonal evolution, epigenetic changes, activated signalling pathways and microenvironmental interactions.

  • CLL is preceded by an asymptomatic precursor termed monoclonal B cell lymphocytosis (MBL). Traditionally, the two most aggressive clinical types of CLL are those resistant to fludarabine or those transforming to aggressive lymphomas of the diffuse large B cell lymphoma (DLBCL) type, known as Richter syndrome.

  • Although CLL may originate at the haematopoietic stem cell (HSC) stage, the final mature B cell of origin of IGHV-M CLL seems to be a post-GC CD5+CD27+ B cell, and that of IGHV-UM CLL could be a pre-GC CD5+CD27 B cell or a GC-independent memory B cell.

  • B cell receptor (BCR) signalling has an important role in the pathogenesis of CLL, as demonstrated by the presence of a highly restricted and biased repertoire of surface immunoglobulin (sIg) in CLL cells, evidence of autonomous BCR signalling and dramatic clinical responses obtained with BCR pathway inhibitors.

  • The CLL genome displays a relatively low mutational burden and is characterized by a small number of frequently mutated putative 'driver' genes and a large number of rarely altered genes. The CLL epigenome is characterized by widespread hypomethylation of DNA in genes and enhancer loci.

  • A subset of genes mutated in CLL confer a poor outcome in patients with CLL and can improve the classic cytogenetics-based prognostic classification of patients with CLL. Also subclonal high-risk genetic lesions can have a negative impact on the outcome of patients with CLL.

  • Intra-sample genetic and epigenetic heterogeneity are both associated with overall poor survival of patients with CLL.

Abstract

Recent investigations have provided an increasingly complete picture of the genetic landscape of chronic lymphocytic leukaemia (CLL). These analyses revealed that the CLL genome displays a high degree of heterogeneity between patients and within the same patient. In addition, they highlighted molecular mechanisms and functionally relevant biological programmes that may be important for the pathogenesis and therapeutic targeting of this disease. This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of CLL. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches.

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Figure 1: The cellular origin of chronic lymphocytic leukaemia.
Figure 2: The genetic landscape of chronic lymphocytic leukaemia.
Figure 3: NOTCH1 and SF3B1 mutations in chronic lymphocytic leukaemia.
Figure 4: NF-κB pathway mutations in chronic lymphocytic leukaemia.
Figure 5: Pathways involved in chronic lymphocytic leukaemia initiation, chemoresistance and transformation.
Figure 6: Clinical implications of recurrent genetic lesions in chronic lymphocytic leukaemia.

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References

  1. Howlader, N. et al. SEER Cancer Statistics Review, 1975–2010. National Cancer Institute Surveillance, Epidemiology and End Results Program [online] (2013).

    Google Scholar 

  2. Yang, S. M., Li, J. Y., Gale, R. P. & Huang, X. J. The mystery of chronic lymphocytic leukemia (CLL): why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology? Blood Rev. 29, 205–213 (2015).

    Article  PubMed  Google Scholar 

  3. Goldin, L. R., Pfeiffer, R. M., Li, X. & Hemminki, K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 104, 1850–1854 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Hallek, M. 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 111, 5446–5456 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hallek, M. Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am. J. Hematol. 90, 446–460 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Campo, E. et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117, 5019–5032 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Damle, R. N. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840–1847 (1999).

    CAS  PubMed  Google Scholar 

  8. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G. & Stevenson, F. K. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848–1854 (1999).

    CAS  PubMed  Google Scholar 

  9. Strati, P. & Shanafelt, T. D. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 126, 454–462 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stilgenbauer, S. & Zenz, T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2010, 481–488 (2010).

    Article  Google Scholar 

  11. Rossi, D. & Gaidano, G. Richter syndrome. Adv. Exp. Med. Biol. 792, 173–191 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Tsimberidou, A. M. et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J. Clin. Oncol. 24, 2343–2351 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Hallek, M. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164–1174 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Hendriks, R. W., Yuvaraj, S. & Kil, L. P. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat. Rev. Cancer 14, 219–232 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Byrd, J. C. et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med. 371, 213–223 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Farooqui, M. Z. et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 16, 169–176 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Burger, J. A. et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N. Engl. J. Med. 373, 2425–2437 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brown, J. R. et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 123, 3390–3397 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. O'Brien, S. et al. Update on a Phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 124, 1994a (2014).

  22. O'Brien, S. M. et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood 126, 2686–2694 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Byrd, J. C. et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 323–332 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. [No authors listed] ABT-199 shows effectiveness in CLL. Cancer Discov. 4, OF7 (2014).

  26. Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311–322 (2016). References 15–23 and 26 highlight the excellent results obtained in the clinics with novel agents impinging on the BCR pathway or inhibiting the anti-apoptotic protein BCL-2 in CLL.

    Article  CAS  PubMed  Google Scholar 

  27. Burger, J. A., Ghia, P., Rosenwald, A. & Caligaris-Cappio, F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood 114, 3367–3375 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Burger, J. A. & Chiorazzi, N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 34, 592–601 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vardi, A. et al. Immunogenetic studies of chronic lymphocytic leukemia: revelations and speculations about ontogeny and clinical evolution. Cancer Res. 74, 4211–4216 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Ten Hacken, E. & Burger, J. A. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim. Biophys. Acta 1863, 401–413 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kikushige, Y. et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20, 246–259 (2011). The first study supporting an early origin of CLL from HSCs, using in vivo xenotransplantation of CLL-derived HSCs in immunodeficient mice.

    Article  CAS  PubMed  Google Scholar 

  32. Damm, F. et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov. 4, 1088–1101 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matutes, E. et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 8, 1640–1645 (1994).

    CAS  PubMed  Google Scholar 

  36. Caligaris-Cappio, F., Gobbi, M., Bofill, M. & Janossy, G. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia. J. Exp. Med. 155, 623–628 (1982).

    Article  CAS  PubMed  Google Scholar 

  37. Stall, A. M. et al. Ly-1 B-cell clones similar to human chronic lymphocytic leukemias routinely develop in older normal mice and young autoimmune (New Zealand Black-related) animals. Proc. Natl Acad. Sci. USA 85, 7312–7316 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Caligaris-Cappio, F. B-chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood 87, 2615–2620 (1996).

    CAS  PubMed  Google Scholar 

  39. Baumgarth, N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 11, 34–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Klein, U. et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J. Exp. Med. 194, 1625–1638 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rosenwald, A. et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J. Exp. Med. 194, 1639–1647 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Klein, U., Rajewsky, K. & Kuppers, R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679–1689 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Seifert, M. et al. Cellular origin and pathophysiology of chronic lymphocytic leukemia. J. Exp. Med. 209, 2183–2198 (2012). References 40, 41 and 43 provide clues about the cellular origin of CLL using gene expression profiling of CLL samples and mature B cell subsets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kulis, M. et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 44, 1236–1242 (2012). This study describes the CLL epigenome and identifies distinct epigenetic classes characterized by different genetic, immunological and clinical features.

    Article  CAS  PubMed  Google Scholar 

  45. Chiorazzi, N. & Ferrarini, M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 117, 1781–1791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Forconi, F. et al. The normal IGHV1-69-derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL. Blood 115, 71–77 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Duhren-von Minden, M. et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489, 309–312 (2012). This study supports the importance of autonomous, possibly antigen-independent BCR signalling in CLL pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  48. Bichi, R. et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc. Natl Acad. Sci. USA 99, 6955–6960 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Speedy, H. E., Sava, G. & Houlston, R. S. Inherited susceptibility to CLL. Adv. Exp. Med. Biol. 792, 293–308 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Goldin, L. R., Bjorkholm, M., Kristinsson, S. Y., 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 94, 647–653 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Raval, A. et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129, 879–890 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Di Bernardo, M. C. et al. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 40, 1204–1210 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Crowther-Swanepoel, D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Slager, S. L. et al. Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia. Blood 120, 843–846 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Berndt, S. I. et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat. Genet. 45, 868–876 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Speedy, H. E. et al. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 46, 56–60 (2014). References 52–56 report the results of GWAS identifying multiple SNPs significantly associated with increased risk of CLL development.

    Article  CAS  PubMed  Google Scholar 

  57. Shaffer, A. L., Emre, N. C., Romesser, P. B. & Staudt, L. M. IRF4: Immunity. Malignancy! Therapy? Clin. Cancer Res. 15, 2954–2961 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. De Silva, N. S., Simonetti, G., Heise, N. & Klein, U. The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol. Rev. 247, 73–92 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Simonetti, G. et al. IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. J. Exp. Med. 210, 2887–2902 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shukla, V., Ma, S., Hardy, R. R., Joshi, S. S. & Lu, R. A role for IRF4 in the development of CLL. Blood 122, 2848–2855 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Dohner, H. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 343, 1910–1916 (2000). This study proposed a cytogenetics-based hierarchical model of classification of CLL patients in distinct risk classes.

    Article  CAS  PubMed  Google Scholar 

  63. Fabbri, G. et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208, 1389–1401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Puente, X. S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Quesada, V. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47–52 (2012).

    Article  CAS  Google Scholar 

  67. Landau, D. A. et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152, 714–726 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Landau, D. A. et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (2015) References 61 and 63–68 report somatic genetic lesions identified in the coding genome or in the entire genome of patients with CLL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ouillette, P. et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 118, 3051–3061 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Edelmann, J. et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood 120, 4783–4794 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Papavasiliou, F. N. & Schatz, D. G. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109 (Suppl.), S35–S44 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Xu, Z., Zan, H., Pone, E. J., Mai, T. & Casali, P. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12, 517–531 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schatz, D. G. & Ji, Y. Recombination centres and the orchestration of V(D)J recombination. Nat. Rev. Immunol. 11, 251–263 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Hallek, M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood 122, 3723–3734 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Rawstron, A. C. et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N. Engl. J. Med. 359, 575–583 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Klein, U. et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17, 28–40 (2010) This study provides in vivo evidence of the causative role of del13q14 in the development of CLL.

    Article  CAS  PubMed  Google Scholar 

  79. Migliazza, A. et al. Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia. Blood 97, 2098–2104 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Kalachikov, S. et al. Cloning and gene mapping of the chromosome 13q14 region deleted in chronic lymphocytic leukemia. Genomics 42, 369–377 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Calin, G. A. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Palamarchuk, A. et al. 13q14 deletions in CLL involve cooperating tumor suppressors. Blood 115, 3916–3922 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hammarsund, M. et al. Characterization of a novel B-CLL candidate gene—DLEU7—located in the 13q14 tumor suppressor locus. FEBS Lett. 556, 75–80 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Mertens, D. et al. Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia. Blood 99, 4116–4121 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Allegra, D. et al. Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. Leukemia 28, 99–107 (2013).

    Google Scholar 

  86. Ouillette, P. et al. Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14. Cancer Res. 68, 1012–1021 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Ouillette, P. et al. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clin. Cancer Res. 17, 6778–6790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dal Bo, M. et al. 13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia. Genes Chromosomes Cancer 50, 633–643 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Lia, M. et al. Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines. Blood 119, 2981–2990 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Del Giudice, I. et al. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica 97, 437–441 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Strati, P. et al. Second cancers and Richter transformation are the leading causes of death in patients with trisomy 12 chronic lymphocytic leukemia. Clin. Lymphoma Myeloma Leuk. 15, 420–427 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Chigrinova, E. et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 122, 2673–2682 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Fabbri, G. et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J. Exp. Med. 210, 2273–2288 (2013) References 93 and 94 are the first studies describing the genetic lesions associated with CLL transformation to RS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wierda, W. G. et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J. Clin. Oncol. 29, 4088–4095 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Stankovic, T. & Skowronska, A. The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia. Leuk. Lymphoma 55, 1227–1239 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14, 197–210 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Skowronska, A. et al. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J. Clin. Oncol. 30, 4524–4532 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Stankovic, T. et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 353, 26–29 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Bullrich, F. et al. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res. 59, 24–27 (1999).

    CAS  PubMed  Google Scholar 

  101. Austen, B. et al. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 106, 3175–3182 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Austen, B. et al. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. J. Clin. Oncol. 25, 5448–5457 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Guarini, A. et al. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. Haematologica 97, 47–55 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rossi, D. et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood 119, 2854–2862 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Gaidano, G. et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 88, 5413–5417 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wattel, E. et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84, 3148–3157 (1994).

    CAS  PubMed  Google Scholar 

  107. Dohner, H. et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 85, 1580–1589 (1995).

    CAS  PubMed  Google Scholar 

  108. Ouillette, P. et al. Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks. Clin. Cancer Res. 16, 835–847 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zenz, T. et al. Treatment resistance in chronic lymphocytic leukemia: the role of the p53 pathway. Leuk. Lymphoma 50, 510–513 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Zenz, T. et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, 53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood 114, 2589–2597 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Rossi, D. et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 117, 3391–3401 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Zenz, T. et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 112, 3322–3329 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Dicker, F. et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia 23, 117–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Rossi, D. et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin. Cancer Res. 15, 995–1004 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Malcikova, J. et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood 114, 5307–5314 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Zenz, T. et al. TP53 mutation and survival in chronic lymphocytic leukemia. J. Clin. Oncol. 28, 4473–4479 (2010).

    Article  PubMed  Google Scholar 

  117. Pospisilova, S. et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 26, 1458–1461 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Rossi, D. et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 123, 2139–2147 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Malcikova, J. et al. Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia 29, 877–885 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Guieze, R. et al. Presence of multiple recurrent mutations revealed by targeted NGS confers poor trial outcome of relapsed/refractory CLL. Blood 126, 2210–2217 (2015).

    Google Scholar 

  121. Di Ianni, M. et al. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br. J. Haematol. 146, 689–691 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Riches, J. C. et al. Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations. Blood 123, 4101–4110 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. O'Neil, J. et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J. Exp. Med. 204, 1813–1824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Thompson, B. J. et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J. Exp. Med. 204, 1825–1835 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rosati, E. et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113, 856–865 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Arruga, F. et al. Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia 28, 1060–1070 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Gomez-del Arco, P. et al. Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. Immunity 33, 685–698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ashworth, T. D. et al. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 116, 5455–5464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jeannet, R. et al. Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL. Blood 116, 5443–5454 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Guy, C. S. et al. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat. Immunol. 14, 262–270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Fortini, M. E. & Bilder, D. Endocytic regulation of Notch signaling. Curr. Opin. Genet. Dev. 19, 323–328 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Maura, F. et al. Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia. PLoS ONE 10, e0118801 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Pozzo, F. et al. NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation. Leukemia 30, 182–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Stilgenbauer, S. et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 123, 3247–3254 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Cazzola, M. et al. Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood 121, 260–269 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shin, C. & Manley, J. L. Cell signalling and the control of pre-mRNA splicing. Nat. Rev. Mol. Cell Biol. 5, 727–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Golas, M. M., Sander, B., Will, C. L., Luhrmann, R. & Stark, H. Molecular architecture of the multiprotein splicing factor SF3b. Science 300, 980–984 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Te Raa, G. D. et al. The impact of SF3B1 mutations in CLL on the DNA-damage response. Leukemia 29, 1133–1142 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Ramsay, A. J. et al. Frequent somatic mutations in components of the RNA processing machinery in chronic lymphocytic leukemia. Leukemia 27, 1600–1603 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Mansouri, L. et al. Functional loss of IkappaBepsilon leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia. J. Exp. Med. 212, 833–843 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Annunziata, C. M. et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Keats, J. J. et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 12, 131–144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rossi, D. et al. Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma. Blood 118, 4930–4934 (2011).

    Article  PubMed  Google Scholar 

  146. Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nat. Rev. Immunol. 12, 282–294 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Treon, S. P. et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N. Engl. J. Med. 367, 826–833 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Alves, B. N. et al. IkappaBepsilon is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J. Immunol. 192, 3121–3132 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Herishanu, Y. et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117, 563–574 (2011). This gene expression profiling study of CLL cells isolated from different anatomical compartments supports the importance of the microenvironment in the activation of pathways relevant for CLL survival such as the BCR and the NF-κB pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Loayza, D. & De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Lei, M., Podell, E. R. & Cech, T. R. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat. Struct. Mol. Biol. 11, 1223–1229 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Ramsay, A. J. et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat. Genet. 45, 526–530 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Rodriguez, D. et al. Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia. Blood 126, 195–202 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Clifford, R. et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123, 1021–1031 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang, L. et al. Somatic mutation as a mechanism of Wnt/beta-catenin pathway activation in CLL. Blood 124, 1089–1098 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. O'Brien, P., Morin, P. Jr, Ouellette, R. J. & Robichaud, G. A. The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease. Cancer Res. 71, 7345–7350 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome - biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kanduri, M. et al. Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia. Blood 115, 296–305 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Cahill, N. et al. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. Leukemia 27, 150–158 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Landau, D. A. et al. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell 26, 813–825 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Oakes, C. C. et al. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 4, 348–361 (2014). References 161 and 162 highlight the importance of intra-tumour CLL epigenetic heterogeneity in predicting genetic clonal evolution and clinical outcome.

    Article  CAS  PubMed  Google Scholar 

  163. Queiros, A. C. et al. A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact. Leukemia 29, 598–605 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Nieto, W. G. et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood 114, 33–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Vardi, A. et al. Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL. Blood 121, 4521–4528 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Landgren, O. et al. B-cell clones as early markers for chronic lymphocytic leukemia. N. Engl. J. Med. 360, 659–667 (2009). This study demonstrates by flow-cytometric and molecular analysis of IGHV genes that virtually all cases of CLL are preceded by MBL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lionetti, M. et al. High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications. Br. J. Haematol. 165, 629–639 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Ojha, J. et al. Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression. Leukemia 28, 2395–2398 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ojha, J. et al. Identification of recurrent truncated DDX3X mutations in chronic lymphocytic leukaemia. Br. J. Haematol. 169, 445–448 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Ojha, J. et al. Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia. Blood 125, 492–498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Rossi, D. et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 119, 521–529 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Messina, M. et al. Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood 123, 2378–2388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Greco, M. et al. Analysis of SF3B1 mutations in monoclonal B-cell lymphocytosis. Hematol. Oncol. 31, 54–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Guieze, R. & Wu, C. J. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 126, 445–453 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Rasi, S. et al. Analysis of NOTCH1 mutations in monoclonal B-cell lymphocytosis. Haematologica 97, 153–154 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rossi, D. et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 118, 6904–6908 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wang, J. et al. Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia. eLife http://doi.dx.org/10.7554/eLife.02869 (2014).

  178. Solh, M. et al. The impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011). Leuk. Lymphoma 54, 252–254 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Weissmann, S. et al. Prognostic impact and landscape of NOTCH1 mutations in chronic lymphocytic leukemia (CLL): a study on 852 patients. Leukemia 27, 2393–2396 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. Villamor, N. et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 27, 1100–1106 (2013).

    Article  CAS  PubMed  Google Scholar 

  181. Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature 464, 1052–1057 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Monti, S. et al. Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell 22, 359–372 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Rossi, D. et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin. Cancer Res. 15, 4415–4422 (2009).

    Article  CAS  PubMed  Google Scholar 

  184. Rossi, D. et al. Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. Blood 121, 4902–4905 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Gounari, M. et al. Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8. Blood 125, 3580–3587 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Rossi, D. et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121, 1403–1412 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Jeromin, S. et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 28, 108–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  188. Baliakas, P. et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 29, 329–336 (2015) References 186–188 report the first efforts to integrate novel mutational data into the traditional FISH-based scheme of classification of patients with CLL into different risk classes.

    Article  CAS  PubMed  Google Scholar 

  189. Oscier, D. G. et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 121, 468–475 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Schnaiter, A. et al. NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG. Blood 122, 1266–1270 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Dreger, P. et al. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood 121, 3284–3288 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Maddocks, K. J. et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 1, 80–87 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Byrd, J. C. et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125, 2497–2506 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Woyach, J. A. et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N. Engl. J. Med. 370, 2286–2294 (2014) This study identifies a novel mechanism of acquisition of resistance of CLL cells to the BTK inhibitor ibrutinib.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu, T. M. et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 126, 61–68 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Cheng, S. et al. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia 29, 895–900 (2015).

    Article  CAS  PubMed  Google Scholar 

  197. Fama, R. et al. Ibrutinib-naive chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance. Blood 124, 3831–3833 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002).

    Article  CAS  PubMed  Google Scholar 

  199. Hofmann, W. K. et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 102, 659–661 (2003).

    Article  CAS  PubMed  Google Scholar 

  200. Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling—are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3, 576–583 (2007).

    Article  CAS  PubMed  Google Scholar 

  202. Larrayoz, M. et al. The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukemia cells through downregulation of Mcl-1. Leukemia 30, 351–360 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Rozman, C. & Montserrat, E. Chronic lymphocytic leukemia. N. Engl. J. Med. 333, 1052–1057 (1995).

    Article  CAS  PubMed  Google Scholar 

  204. Binet, J. L. et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48, 198–206 (1981).

    Article  CAS  PubMed  Google Scholar 

  205. Rai, K. R. et al. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219–234 (1975).

    CAS  PubMed  Google Scholar 

  206. Stein, H. et al. Immunohistologic analysis of the organization of normal lymphoid tissue and non-Hodgkin's lymphomas. J. Histochem. Cytochem. 28, 746–760 (1980).

    Article  CAS  PubMed  Google Scholar 

  207. Burger, J. A., Burger, M. & Kipps, T. J. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94, 3658–3667 (1999).

    CAS  PubMed  Google Scholar 

  208. Kurtova, A. V. et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood 114, 4441–4450 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. 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 91, 2387–2396 (1998).

    CAS  PubMed  Google Scholar 

  210. Lutzny, G. et al. Protein kinase c-beta-dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell 23, 77–92 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Burger, J. A. The, C. L. L. Cell Microenvironment. Adv. Exp. Med. Biol. 792, 25–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  212. Burger, J. A. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2011, 96–103 (2011).

    Article  Google Scholar 

  213. Pizzolo, G. et al. Immunohistologic study of bone marrow involvement in B-chronic lymphocytic leukemia. Blood 62, 1289–1296 (1983).

    CAS  PubMed  Google Scholar 

  214. Ghia, P. et al. Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. Eur. J. Immunol. 32, 1403–1413 (2002).

    Article  CAS  PubMed  Google Scholar 

  215. Patten, P. E. et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111, 5173–5181 (2008).

    Article  CAS  PubMed  Google Scholar 

  216. Os, A. et al. Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. Cell Rep. 4, 566–577 (2013).

    Article  CAS  PubMed  Google Scholar 

  217. Bagnara, D. et al. A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease. Blood 117, 5463–5472 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank U. Klein, L. Pasqualucci, K. Basso and A. Holmes for their critical comments on the manuscript. They apologize to those whose work was not included owing to space limitations.

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Glossary

Non-Hodgkin lymphomas

(NHLs). Haematological malignancies that affect lymphocytes, mainly of the B cell type ( 85%), classified on the basis of histological, genetic and immunophenotypic features.

Small lymphocytic lymphoma

Predominantly nodal variant of chronic lymphocytic leukaemia (CLL), diagnosed in the presence of lymphadenopathy or splenomegaly, with < 5 × 109 CLL cells per litre of peripheral blood.

Diffuse large B cell lymphoma

(DLBCL). Most common type of non-Hodgkin lymphoma (NHL, 40% of cases) originating from germinal centre (GC) B cells and comprising two main disease subgroups, based on similarities to their putative cell of origin: GC B cell-like (GCB) DLBCL, deriving from centroblasts, and activated B cell (ABC) DLBCL, with features resembling those of plasmablastic B cells.

Richter syndrome

Development of an aggressive lymphoma, most commonly a diffuse large B cell lymphoma (DLBCL), in the context of chronic lymphocytic leukaemia (CLL).

Germinal centre

Histological temporary structure arising in lymph node follicles after exposure to a T cell-dependent antigen and dedicated to the generation and selection of B cells producing high-affinity antibodies. Most B cell lymphomas derive from this structure.

CD27+ memory B cells

Pathogen-experienced B cells expressing the CD27 antigen that can be rapidly reactivated to produce high-affinity antibodies.

BCR Ig stereotypes

B cell receptor (BCR) subsets displaying restricted, nearly identical immunoglobulin (Ig) variable heavy chain complementarity-determining region 3 (HCDR3) sequences.

Complementarity-determining regions

(CDRs). Portions of the variable region of the immunoglobulin that contribute to antigen binding.

Autoantigens

Antigens that, despite being normal tissue constituents, can trigger a humoral or a cell-mediated immune response.

Exogenous antigens

Antigens entering the body from the outside (that is, by inhalation, ingestion or injection).

GC reaction

Immunological process in which B cells, in response to T cell-dependent antigens, undergo iterative cycles of targeted mutagenesis and affinity-based selection to produce high-affinity antibodies and differentiate into plasma cells or memory B cells. These cycles take place in defined structures known as germinal centres (GCs).

Burkitt lymphoma

Aggressive non-Hodgkin lymphoma (NHL) deriving from GC dark zone B cells, and including the sporadic, endemic and HIV-associated forms.

Multiple myeloma

Non-Hodgkin lymphoma (NHL) deriving from malignant plasma cells infiltrating the bone marrow, and associated with high levels of monoclonal (M) protein in the blood and/or serum.

Somatic hypermutation

Genetic process introducing mutations (mainly single nucleotide changes) in the first 2 kb from the transcriptional start site of the genes encoding the variable regions of the immunoglobulin receptors (IGHV).

Class-switch recombination

Genetic process by which a B cell switches from the production of immunoglobulin (Ig)M to the production of IgG, IgE or IgA.

VDJ recombination

Genetic process mediating the recombination of the immunoglobulin loci to place one variable (V), one diversity (D) and one joining (J) gene next to each other.

Chromothripsis

From the Greek 'thripsis' ('shattering into pieces'), chromothripsis is a complex genomic aberration that appears to have originated in a single event and is defined by the occurrence of rearrangements in localized chromosomal regions (approximately hundreds in one or two chromosomes), a low number of copy number states across the rearranged region and alternation of regions where heterozygosity is preserved with regions presenting loss of heterozygosity.

Chromoplexis

From the Greek 'plek' ('to weave' or 'to braid'), chromoplexis is a complex genomic aberration that appears to have originated in a single event and is defined by the presence of unclustered chained chromosomal rearrangements, usually numbering in the tens, that affects multiple chromosomes.

U2 snRNP

RNA–protein complex composed of the small nuclear RNA (snRNA) U2 and several interacting proteins, which has a relevant role in the early stages of RNA splicing.

Toll-like receptor (TLR) pathway

Inflammatory cascade triggered by the recognition by Toll-like receptors (TLRs) of various molecules containing pathogen-associated molecular patterns (PAMPs) and/or endogenous damage-associated molecular patterns (DAMPs) and having a critical role in innate immune responses.

Waldenström's macroglobulinaemia

Non-Hodgkin lymphoma (NHL) characterized by the presence of lymphoplasmacytic cells infiltrating the bone marrow along with the production of a serum monoclonal immunoglobulin M (IgM).

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Fabbri, G., Dalla-Favera, R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer 16, 145–162 (2016). https://doi.org/10.1038/nrc.2016.8

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