Advanced search

Vol 55, No 3 (2017)
Review paper
Published online: 2017-10-09

open access

View PDF Download PDF file
Page views 2013
Article views/downloads 1904
Get Citation

Connect on Social Media

Connect on Social Media

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

Ewelina Zakrzewska1, Marta Pirog1, Joanna Purkot1, Krzysztof Giannopoulos12
DOI: 10.5603/FHC.a2017.0019
Pubmed: 28994094
Folia Histochem Cytobiol 2017;55(3):95-106.

Abstract

Cytogenetic lesions do not completely explain clinical heterogeneity of chronic lymphocytic leukemia (CLL). The 2016 revision of the World Health Organization classification 2008 indicated that molecular lesions of TP53, NOTCH1, SF3B1 and BIRC3 have potential clinical relevance and could be integrated into an updated risk profile. The negative clinical implications of TP53 disruptions are well constituted and patients with these mutations should be considered for novel, small molecule signal transduction inhibitors therapies. Mutations of NOTCH1, SF3B1 and BIRC3 are associated with poor prognosis. Patients with mutated SF3B1 or NOTCH1 genes present shorter time to first treatment compared to unmutated group. NOTCH1 mutations are related to a high risk of Richter’s syndrome transformation, especially in case of TP53 disruptions’ coexistence. Large studies on MYD88 mutations in CLL have not explained clearly their clinical importance.The aim of this paper is to provide a comprehensive review on novel molecular aberrations identified in CLL.

Keywords: chronic lymphocytic leukemiaTP53NOTCH1SF3B1BIRC3MYD88prognostic factors

Article available in PDF format

View PDF Download PDF file

References

  1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352(8): 804–815.
    CrossRefPubMed
  2. Abrisqueta P, Pereira A, Rozman C, et al. Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of Barcelona experience. Blood. 2009; 114(10): 2044–2050.
    CrossRefPubMed
  3. Shanafelt TD, Jenkins G, Call TG, et al. Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer. 2009; 115(2): 363–372.
    CrossRefPubMed
  4. Hallek M, Cheson BD, Catovsky D, et al. International Workshop on Chronic Lymphocytic Leukemia. 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): 5446–5456.
    CrossRefPubMed
  5. Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet. 2008; 371(9617): 1017–1029.
    CrossRefPubMed
  6. Rassenti LZ, Huynh L, Toy TL, et al. 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.
    CrossRefPubMed
  7. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26): 1910–1916.
    CrossRefPubMed
  8. Foà R, Del Giudice I, Guarini A, et al. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica. 2013; 98(5): 675–685.
    CrossRefPubMed
  9. 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(7): 1389–1401.
    CrossRefPubMed
  10. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011; 475(7354): 101–105.
    CrossRefPubMed
  11. 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(1): 47–52.
    CrossRefPubMed
  12. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013; 121(8): 1403–1412.
    CrossRefPubMed
  13. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20): 2375–2390.
    CrossRefPubMed
  14. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016; 17(6): 779–790.
    CrossRefPubMed
  15. Lamb P, Crawford L. Characterization of the human p53 gene. Mol Cell Biol. 1986; 6(5): 1379–1385.
    CrossRef
  16. Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998; 2(3): 305–316.
    CrossRefPubMed
  17. Venot C, Maratrat M, Dureuil C, et al. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J. 1998; 17(16): 4668–4679.
    CrossRefPubMed
  18. Laptenko O, Shiff I, Freed-Pastor W, et al. The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. Mol Cell. 2015; 57(6): 1034–1046.
    CrossRefPubMed
  19. Khoury MP, Bourdon JC. p53 isoforms: an intracellular microprocessor? Genes Cancer. 2011; 2(4): 453–465.
    CrossRefPubMed
  20. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014; 14(5): 359–370.
    CrossRefPubMed
  21. Xu-Monette ZY, Medeiros LJ, Li Y, et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 2012; 119(16): 3668–3683.
    CrossRefPubMed
  22. Velletri T, Xie N, Wang Y, et al. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development. Cell Death Dis. 2016; 7: e2015.
    CrossRefPubMed
  23. Oren M, Rotter V. Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol. 2010; 2(2): a001107.
    CrossRefPubMed
  24. Soussi T, Dehouche K, Béroud C. p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis. Hum Mutat. 2000; 15(1): 105–113, doi: 10.1002/(SICI)1098-1004(200001)15:1<105::AID-HUMU19>3.0.CO;2-G.
    PubMed
  25. Pekova S, Mazal O, Cmejla R, et al. A comprehensive study of TP53 mutations in chronic lymphocytic leukemia: Analysis of 1287 diagnostic and 1148 follow-up CLL samples. Leuk Res. 2011; 35(7): 889–898.
    CrossRefPubMed
  26. Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012; 119(9): 2114–2121.
    CrossRefPubMed
  27. Rossi D, Cerri M, Deambrogi C, 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. 2009; 15(3): 995–1004.
    CrossRefPubMed
  28. Dicker F, Herholz H, Schnittger S, 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. 2009; 23(1): 117–124.
    CrossRefPubMed
  29. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011; 29(16): 2223–2229.
    CrossRefPubMed
  30. Zenz T, Häbe S, Denzel T, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009; 114(13): 2589–2597.
    CrossRefPubMed
  31. Malcikova J, Pavlova S, Kozubik KS, et al. TP53 mutation analysis in clinical practice: lessons from chronic lymphocytic leukemia. Hum Mutat. 2014; 35(6): 663–671.
    CrossRefPubMed
  32. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007; 28(6): 622–629.
    CrossRefPubMed
  33. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999; 94(6): 1848–1854.
    PubMed
  34. Langerak AW, Davi F, Ghia P, et al. European Research Initiative on CLL (ERIC). Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases. Leukemia. 2011; 25(6): 979–984.
    CrossRefPubMed
  35. Cesano A, Perbellini O, Evensen E, et al. Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies. Haematologica. 2013; 98(4): 626–634.
    CrossRefPubMed
  36. Stamatopoulos K, Agathangelidis A, Rosenquist R, et al. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia. 2016; 31(2): 282–291.
    CrossRef
  37. Malcikova J, Stalika E, Davis Z, et al. The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors. Br J Haematol. 2014; 166(4): 621–625.
    CrossRefPubMed
  38. Rosati E, Sabatini R, Rampino G, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009; 113(4): 856–865.
    CrossRefPubMed
  39. Hajdu M, Sebestyén A, Barna G, et al. Activity of the notch-signalling pathway in circulating human chronic lymphocytic leukaemia cells. Scand J Immunol. 2007; 65(3): 271–275.
    CrossRefPubMed
  40. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006; 107(6): 2223–2233.
    CrossRefPubMed
  41. Sanchez-Irizarry C, Carpenter AC, Weng AP, et al. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol. 2004; 24(21): 9265–9273.
    CrossRefPubMed
  42. Gianfelici V. Activation of the NOTCH1 pathway in chronic lymphocytic leukemia. Haematologica. 2012; 97(3): 328–330.
    CrossRefPubMed
  43. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J Exp Med. 2011; 208(10): 1931–1935.
    CrossRefPubMed
  44. Di Ianni M, Baldoni S, Rosati E, et al. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol. 2009; 146(6): 689–691.
    CrossRefPubMed
  45. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2011; 119(2): 521–529.
    CrossRef
  46. Paganin M, Ferrando A. Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. Blood Rev. 2011; 25(2): 83–90.
    CrossRefPubMed
  47. Pear WS, Aster JC. T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling. Curr Opin Hematol. 2004; 11(6): 426–433.
    CrossRefPubMed
  48. Rose-Zerilli MJJ, Forster J, Parker H, et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 2013; 121(3): 468–475.
    CrossRefPubMed
  49. Del Giudice I, Rossi D, Chiaretti S, 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. 2012; 97(3): 437–441.
    CrossRefPubMed
  50. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood. 2012; 119(2): 329–331.
    CrossRefPubMed
  51. Mansouri L, Cahill N, Gunnarsson R, et al. NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia. 2013; 27(2): 512–514.
    CrossRefPubMed
  52. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012; 158(3): 426–429.
    CrossRefPubMed
  53. 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(21): 3247–3254.
    CrossRefPubMed
  54. Stilgenbauer S, Zenz T, Winkler D, et al. German Chronic Lymphocytic Leukemia Study Group. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009; 27(24): 3994–4001.
    CrossRefPubMed
  55. Schnaiter A, Paschka P, Rossi M, et al. NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG. Blood. 2013; 122(7): 1266–1270.
    CrossRefPubMed
  56. National Center for Biotechnology Information resources. SF3B1 splicing factor 3b subunit 1 [Homo sapiens(human)]. https://www.ncbi.nlm.nih.gov/gene/23451 (September 27, 2017).
  57. Wahl MC, Will CL, Lührmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009; 136(4): 701–718.
    CrossRefPubMed
  58. Cazzola M, Rossi M, Malcovati L, et al. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood. 2013; 121(2): 260–269.
    CrossRefPubMed
  59. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011; 478(7367): 64–69.
    CrossRefPubMed
  60. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011; 365(26): 2497–2506.
    CrossRefPubMed
  61. Tang Q, Rodriguez-Santiago S, Wang J, et al. SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing. Genes Dev. 2016; 30(24): 2710–2723.
    CrossRefPubMed
  62. Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011; 118(24): 6239–6246.
    CrossRef
  63. Foà R, Del Giudice I, Guarini A, et al. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica. 2013; 98(5): 675–685.
    CrossRefPubMed
  64. Tripathi R, Lee-Verges E, Higashi M, et al. New drug discovery approaches targeting recurrent mutations in chronic lymphocytic leukemia. Expert Opin Drug Discov. 2017; 12(10): 1041–1052.
    CrossRefPubMed
  65. Mitsui T, Koiso H, Nakahashi H, et al. SF3B1 and IGHV gene mutation status predict poor prognosis in Japanese CLL patients. Int J Hematol. 2016; 103(2): 219–226.
    CrossRefPubMed
  66. Te Raa GD, Derks IAM, Navrkalova V, et al. The impact of SF3B1 mutations in CLL on the DNA-damage response. Leukemia. 2015; 29(5): 1133–1142.
    CrossRefPubMed
  67. Wang L, Brooks AN, Fan J, et al. Transcriptomic characterization of SF3B1 mutation reveals its pleiotropic effects in chronic lymphocytic leukemia. Cancer Cell. 2016; 30(5): 750–763.
    CrossRefPubMed
  68. Wan Y, Wu CJ. SF3B1 mutations in chronic lymphocytic leukemia. Blood. 2013; 121(23): 4627–4634.
    CrossRefPubMed
  69. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013; 152(4): 714–726.
    CrossRefPubMed
  70. Baliakas P, Hadzidimitriou A, Sutton LA, et al. European Research Initiative on CLL (ERIC). Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015; 29(2): 329–336.
    CrossRefPubMed
  71. 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(26): 6904–6908.
    CrossRefPubMed
  72. Rasi S, Khiabanian H, Ciardullo C, et al. Clinical impact of small subclones harboring NOTCH1 , SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia. Haematologica. 2016; 101(4): e135–e138.
    CrossRef
  73. Campregher PV, Hamerschlak N. Novel prognostic gene mutations identified in chronic lymphocytic leukemia and their impact on clinical practice. Clin Lymphoma Myeloma Leuk. 2014; 14(4): 271–276.
    CrossRefPubMed
  74. Dreger P, Schnaiter A, Zenz T, 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. 2013; 121(16): 3284–3288.
    CrossRefPubMed
  75. National Center for Biotechnology Information resources. BIRC3 baculoviral IAP repeat containing 3 [(human)]. https://www.ncbi.nlm.nih.gov/gene/330 (September 27, 2017).
  76. Silke J, Vaux DL. Two kinds of BIR-containing protein - inhibitors of apoptosis, or required for mitosis. J Cell Sci. 2001; 114(Pt 10): 1821–1827.
    PubMed
  77. Bertrand MJM, Lippens S, Staes An, et al. cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4). PLoS One. 2011; 6(9): e22356.
    CrossRefPubMed
  78. Balakrishnan K, Fu M, Onida F, et al. Reactivation of Smac-mediated apoptosis in chronic lymphocytic leukemia cells: mechanistic studies of Smac mimetic. Oncotarget. 2016; 7(26): 39458–39472.
    CrossRefPubMed
  79. Huang Hk, Joazeiro CA, Bonfoco E, et al. The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J Biol Chem. 2000; 275(35): 26661–26664.
    CrossRefPubMed
  80. Vallabhapurapu S, Matsuzawa A, Zhang W, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol. 2008; 9(12): 1364–1370.
    CrossRefPubMed
  81. Choudhary S, Kalita M, Fang L, et al. Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation. J Biol Chem. 2013; 288(20): 14612–14623.
    CrossRefPubMed
  82. Yamato A, Soda M, Ueno T, et al. Oncogenic activity of BIRC2 and BIRC3 mutants independent of nuclear factor-κB-activating potential. Cancer Sci. 2015; 106(9): 1137–1142.
    CrossRefPubMed
  83. Rose-Zerilli MJJ, Forster J, Parker H, et al. ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Haematologica. 2014; 99(4): 736–742.
    CrossRefPubMed
  84. Nabhan C, Raca G, Wang YL. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era. JAMA Oncol. 2015; 1(7): 965–974.
    CrossRefPubMed
  85. Del Po, Ragusa D, Buccisano F, et al. Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL). Blood. 2013; 122: 1370.
  86. Landau DA, Wu CJ. Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. Genome Med. 2013; 5(5): 47.
    CrossRefPubMed
  87. Chiaretti S, Marinelli M, Del Giudice I, et al. NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukemia undergoing first-line treatment: correlation with biological parameters and response to treatment. Leuk Lymphoma. 2014; 55(12): 2785–2792.
    CrossRefPubMed
  88. Xia Yi, Fan L, Wang Li, et al. Frequencies of SF3B1, NOTCH1, MYD88, BIRC3 and IGHV mutations and TP53 disruptions in Chinese with chronic lymphocytic leukemia: disparities with Europeans. Oncotarget. 2015; 6(7): 5426–5434.
    CrossRefPubMed
  89. Amaya-Chanaga CI, Rassenti LZ. Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers. Best Pract Res Clin Haematol. 2016; 29(1): 79–89.
    CrossRefPubMed
  90. Iwasaki A, Medzhitov R, Iwasaki A, et al. Regulation of adaptive immunity by the innate immune system. Science. 2010; 327(5963): 291–295.
    CrossRefPubMed
  91. Vandenbon A, Teraguchi S, Akira S, et al. Systems biology approaches to toll-like receptor signaling. Wiley Interdiscip Rev Syst Biol Med. 2012; 4(5): 497–507.
    CrossRefPubMed
  92. Ngo VuN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011; 470(7332): 115–119.
    CrossRefPubMed
  93. Treon S, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012; 367(9): 826–833.
    CrossRef
  94. Wang JQ, Jeelall YS, Ferguson LL, et al. Toll-like receptors and cancer: MYD88 mutation and inflammation. Front Immunol. 2014; 5: 367.
    CrossRefPubMed
  95. Jeromin S, Weissmann S, Haferlach C, et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia. 2014; 28(1): 108–117.
    CrossRefPubMed
  96. Putowski M, Podgórniak M, Piróg M, et al. Prognostic impact of NOTCH1, MYD88, and SF3B1 mutations in Polish patients with chronic lymphocytic leukemia. Pol Arch Intern Med. 2017; 127(4): 238–244.
    CrossRefPubMed
  97. Pospisilova S, Gonzalez D, Malcikova J, et al. European Research Initiative on CLL (ERIC). ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia. 2012; 26(7): 1458–1461.
    CrossRefPubMed
  98. Krzywinski M, Schein J, Birol I, et al. Circos: an information aesthetic for comparative genomics. Genome Res. 2009; 19(9): 1639–1645.
    CrossRefPubMed
  99. Rosenquist R, Cortese D, Bhoi S, et al. Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma. 2013; 54(11): 2351–2364.
    CrossRefPubMed

About cookies

Necessary cookies

Allways active

These cookies are necessary for the proper display and operation of the website. Blocking them may cause the website to malfunction.

Analytical cookies

As part of our website, we use analytical tools, such as Google Analytics, that allow us to verify website traffic. These tools may require the use of cookies.

Community cookies

These are cookies associated with the social networks we use. Accepting them will allow us to associate your visit to the site with our social media profiles.

Marketing cookies

These are cookies responsible for carrying out advertising and marketing activities - consenting to their use will allow us to target you with advertisements based on your previous activities within our website.

Copyright © 2023-2024 Via Medica Regulations Cookie policy Privacy Statement Legal Note