The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia

K. Tari; Z. Shamsi; H. Reza Ghafari; A. Atashi; M. Shahjahani; S. Abroun

Authors

K. Tari Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj 66177-13446, Iran
Z. Shamsi Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
H. Reza Ghafari Department of Hematology, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
A. Atashi Department of Basic Medical Sciences, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
M. Shahjahani Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
S. Abroun Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Keywords:

chronic lymphocytic leukemia, epigenetics, genetic mutation

Abstract

Summary. Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

References

Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. New Engl J Med 2000; 343: 1910–6.

Stilgenbauer S, Lichter P, Dohner H. Genomic aberrations in B-cell chronic lymphocytic leukemia. Basic Clin Oncol 2001; 26: 353–76.

Austen B, Skowronska A, Baker C, 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 2007; 25: 5448–57.

Stilgenbauer S, Bullinger L, Benner A, et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia 1999; 13: 1331–4.

Moreno C, Montserrat E. Genetic lesions in chronic lymphocytic leukemia: what’s ready for prime time use? Haematologica 2010; 95: 12–5.

Montserrat E, Vinolas N, Reverter J, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Franc D’Hematol 1987; 30: 359–61.

Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 2002; 100: 1177–84.

Mayr C, Speicher MR, Kofler DM, et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood 2006; 107: 742–51.

Rodríguez-Vicente AE, Díaz MG, Hernández-Rivas JM. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genetics 2013; 206: 49–62.

Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Inv 1998; 102: 1515.

Rajewsky K. Clonal selection and learning in the antibody system. Nature 1996; 381: 751–8.

Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–54.

Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–7.

Kröber A, Seiler T, Benner A, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100: 1410–6.

Hamblin T, Orchard JA, Gardiner A, et al. Immunoglobulin V genes and CD38 expression in CLL. Blood 2000; 95: 2455–7.

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 NAS 2002; 99: 15524–9.

Klein U, Lia M, Crespo M, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 2010; 17: 28–40.

Smonskey MT, Block AW, Deeb G, et al. Monoallelic and biallelic deletions of 13q14.3 in chronic lymphocytic leukemia FISH vs miRNA RT-qPCR detection. Amer J Clin Pathol 2012; 137: 641–6.

Birerdinc A, Nohelty E, Marakhonov A, et al. Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region. Tumor Biol 2010; 31: 33–45.

Dal Bo M, Rossi FM, Rossi D, et al. 13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia. Genes, Chromosomes Cancer 2011; 50: 633–43.

Offit K, Parsa N, Gaidano G, et al. 6q deletions define distinct clinico-pathologic subsets of non-Hodgkin’s lymphoma. Blood 1993; 82: 2157–62.

Döhner H, Stilgenbauer S, Döhner K, et al. Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis. J Mol Med 1999; 77: 266–81.

Gaidano G, Newcomb EW, Gong JZ, et al. Analysis of alterations of oncogenes and tumor suppressor genes in chronic lymphocytic leukemia. Amer J Pathol 1994; 144: 1312.

Hurley JN, Fu SM, Kunkel HG, et al. Chromosome abnormalities of leukaemic B lymphocytes in chronic lymphocytic leukaemia. Nature 1980; 283: 76–8.

Offit K, Louie D, Parsa N, et al. Clinical and morphologic features of B-cell small lymphocytic lymphoma with del (6)(q21q23). Blood 1994; 83: 2611–8.

Deletions of chromosome regions 6q21 and 6q27 in B-CLL detected by FISH: incidence and correlation with clinical parameters in 208 patients. Stilgenbauer S, Bullinger L, Schroder M, et al., eds. Blood 1996: WB Saunders Co Independence Square West Curtis Center, STE 300, Philadelphia: 3399–19106.

Hernandez J, Mecucci C, Criel A, et al. Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria. Leukemia 1995; 9: 2140-6.

Johansson B, Mertens F, Mitelman F. Cytogenetic deletion maps of hematologic neoplasms: circumstantial evidence for tumor suppressor loci. Genes, Chromosomes Cancer 1993; 8: 205-18.

Neilson J, Auer R, White D, et al. Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia 1997; 11: 1929–32.

Stilgenbauer S, Liebisch P, James MR, et al. Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11q22.3-923.1 in lymphoproliferative disorders. Proc NAS 1996; 93: 11837–41.

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: 4342–9.

Gaidano G, Ballerini P, Gong JZ, et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc NAS 1991; 88: 5413–7.

Chan AC, Irving BA, Fraser JD, Weiss A. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein. Proc NAS 1991; 88: 9166–70.

Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. New Engl J Med 2003; 348: 1764–75.

Campana D, Suzukia T, Todisco E, Kitanakac A. CD38 in hematopoiesis. Chem Immunol 2000; 75: 169–88.

Deaglio S, Capobianco A, Bergui L, et al. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood 2003; 102: 2146–55.

Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc NAS USA 2005; 102: 13944–9.

Bonci D, Coppola V, Musumeci M, et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nature Med 2008; 14: 1271–7.

Calin GA, Cimmino A, Fabbri M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc NAS 2008; 105: 5166–71.

Aqeilan R, Calin G, Croce C. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Different 2010; 17: 215–20.

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: 1261–75.

Herling M, Patel K, Khalili J, et al. TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state. Leukemia 2006; 20: 280–5.

Pekarsky Y, Santanam U, Cimmino A, et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res 2006; 66: 11590–3.

Santanam U, Pekarsky Y, Cimmino A, et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by microRNA-29 and microRNA-181. Cancer Res 2007; 67: 5326.

Pekarsky Y, Palamarchuk A, Maximov V, et al. Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL. Proc NAS 2008; 105: 19643–8.

Bichi R, Shinton SA, Martin ES, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc NAS 2002; 99: 6955–60.

Croce CM, Pekarsky Y. Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression. Google Patents 2011.

Santanam U, Zanesi N, Efanov A, et al. Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression. Proc NAS 2010; 107: 12210–5.

Pekarsky Y, Croce CM. Is miR-29 an oncogene or tumor suppressor in CLL? Oncotarget 2010; 1: 224.

Hua Z, Chun W, Fang-yuan C. MicroRNA-146a and hemopoietic disorders. Int J Hematol 2011; 94: 224–9.

Bhagavathi S, Czader M. MicroRNAs in benign and malignant hematopoiesis. Arch Pathol Labor Med 2010; 134: 1276–81.

Labbaye C, Testa U. The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer. J Hematol Oncol 2012; 5: 13.

Zenz T, Mohr J, Eldering E, et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 2009; 113: 3801–8.

Mráz M, Malinová K, Kotaskova J, et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 2009; 23: 1159–63.

Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 2009; 8: 1409–20.

Füllgrabe J, Kavanagh E, Joseph B. Histone onco-modifications. Oncogene 2011; 30: 3391–403.

Sarkar S, Goldgar S, Byler S, et al. Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy. Epigenomics 2013; 5: 87–94.

Sarkar S, Horn G, Moulton K, et al. Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci 2013; 14: 21087–113.

Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 2013; 342: 12348–50.

Heerboth S, Lapinska K, Snyder N, et al. Use of epigenetic drugs in disease: an overview. Gen Epigen 2014; 6: 9.

Samorodnitsky E, Ghosh E, Mazumder S, Sarkar S. Methylation by DNMT1 is more efficient in chronic lymphocytic leukemia cells than in normal cells. J Proteom Bioinform Sci 2014; 10: 2.

Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Gen 2000; 16: 168–74.

Ronchetti D, Tuana G, Rinaldi A, et al. Distinct patterns of global promoter methylation in early stage chronic lymphocytic leukemia. Genes, Chromosomes Cancer 2014; 53: 264–73.

Kulis M, Heath S, Bibikova M, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nature Genetics 2012; 44: 1236–42.

Tsirigotis P, Pappa V, Labropoulos S, et al. Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16INK4A) gene in chronic lymphocytic leukemia. Europ J Haematol 2006; 76: 230–6.

Byler S, Goldgar S, Heerboth S, et al. Genetic and epigenetic aspects of breast cancer progression and therapy. Anticancer Res 2014; 34: 1071–7.

DNA methylation changes in leukaemia. In: Seminars in Cancer Biology. JR Melki, SJ Clark, eds. Elsevier, 2002.

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: 1820–8.

Kantharidis P, El-Osta A, Wall D, et al. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance. Clin Cancer Res 1997; 3: 2025–32.

Yuille MR, Condie A, Stone EM, et al. TCL1 is activated by chromosomal rearrangement or by hypomethylation. Genes, Chromosomes Cancer 2001; 30: 336–41.

Melki JR, Vincent PC, Brown RD, Clark SJ. Hypermethylation of E-cadherin in leukemia. Blood 2000; 95: 3208–13.

Bechter OE, Eisterer W, Dlaska M, et al. CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia. Exp Hematol 2002; 30: 26–33.

Raval A, Lucas DM, Matkovic JJ, et al. TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 3877–85.

Corcoran M, Parker A, Orchard J, et al. ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia. Haematologica 2005; 90: 1078–88.

Cillo C, Cantile M, Faiella A, Boncinelli E. Homeobox genes in normal and malignant cells. J Cell Physiol 2001; 188: 161–9.

Strathdee G, Holyoake TL, Sim A, et al. Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. Clin Cancer Res 2007; 13: 5048–55.

Fülöp Z, Csernus B, Timar B, et al. Microsatellite instability and hMLH1 promoter hypermethylation in Richter’s transformation of chronic lymphocytic leukemia. Leukemia 2003; 17: 411–5.

Raval A, Tanner SM, Byrd JC, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 2007; 129: 879–90.

Liu T-H, Raval A, Chen S-S, et al. CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia. Cancer Res 2006; 66: 653–8.

Chim C, Pang R, Liang R. Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia. J Clin Pathol 2008; 61: 1214–9.

Moskalev EA, Luckert K, Vorobjev IA, et al. Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia. BMC Cancer 2012; 12: 213.

Margaret KY, Bergonia H, Szabo A, Phillips JD. Progressive disease in chronic lymphocytic leukemia is correlated with the DNA methylation index. Leukemia Res 2007; 31: 773–7.

Pallasch CP, Patz M, Park YJ, et al. miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood 2009; 114: 3255–64.

Baer C, Claus R, Frenzel LP, et al. Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. Cancer Res 2012; 72: 3775–85.

Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New Engl J Med 2005; 353: 1793–801.

Hershko A. Some lessons from my work on the biochemistry of the ubiquitin system. J Biol Chem 2009; 284: 10291–5.

Silverman JS, Skaar JR, Pagano M. SCF ubiquitin ligases in the maintenance of genome stability. Trends Biochem Sci 2012; 37: 66–73.

Lim MS, Adamson A, Lin Z, et al. Expression of Skp2, a p27Kip1 ubiquitin ligase, in malignant lymphoma: correlation with p27Kip1 and proliferation index. Blood 2002; 100: 2950–6.

Kitagawa K, Kotake Y, Kitagawa M. Ubiquitin‐mediated control of oncogene and tumor suppressor gene products. Cancer Science 2009; 100: 1374–81.

Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 2009; 27: 5459–68.

Bokelmann I, Mahlknecht U. Valproic acid sensitizes chronic lymphocytic leukemia cells to apoptosis and restores the balance between pro-and antiapoptotic proteins. Mol Med 2008; 14: 20.

Jordaan G, Liao W, Coriaty N, Sharma S. Identification of histone epigenetic modifications with chromatin immunoprecipitation PCR array in chronic lymphocytic leukemia specimens. J Cancer Sci Ther 2014; 6: 325–32.

Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010; 28: 1749–55.

Martinez-Torres A-C, Quiney C, Attout T, et al. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans. PLoS Med 2015; 12: e1001796.

Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4070–8.

Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: Updated results of the CLL11 study. Leukemia 2015; 29: 1602–4.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. New Engl J Med 2014; 370: 1101–10.

Woyach JA, Bojnik E, Ruppert AS, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 2014; 3: 1207–13.

Yang Q, Modi P, Newcomb T, et al. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res 2015; 21: 1537–42.