Abstract
Chronic lymphocytic leukemia (CLL) is a heterogeneous type of malignant B cell cancer that occurs in older adults. CLL patients may stay free of cancer symptoms for a long period of time and require no treatment. However, malignant progression of CLL strikes indefinitely in some patients, and such CLL responds poorly to conventional chemotherapies and will eventually acquire chemoresistance. Currently, no efficient therapeutic options are available to prevent or stop CLL from progressing into an uncontrollable chemoresistant stage. CLL thus remains to be a challenging disease that requires research explorations for efficient therapeutic methods. CLL cells harbor gene deletions and mutations that continue to accumulate in the course of disease progression and chemotherapy. While it is difficult to directly correct genetic defects in CLL, we reviewed recent research advancements focusing on several crucial molecular pathways that support the proliferative potential of CLL. Since molecules in these pathways can contribute to proliferation, survival and chemoresistance of CLL, they are potentially useful therapeutic targets. We discussed promising methods that have been developed to target functions of these molecules. Encouraging results emerged from these continuing research efforts have provided a new hope for more efficient treatments and increased survival rates for CLL patients.
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References
Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzi N (2003) Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102:3333–3339
Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R, Russo G, Hardy RR, Croce CM (2002) Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci U S A 99:6955–6960
Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A (2003) The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood 102:956–963
Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, Weiss A, Kipps TJ (2005) ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105:2036–2041
Cotter FE, Auer RL (2007) Genetic alteration associated with chronic lymphocytic leukemia. Cytogenet Genome Res 118:310–319
Coutinho A, Gronowicz E, Bullock WW, Moller G (1974) Mechanism of thymus-independent immunocyte triggering. Mitogenic activation of B cells results in specific immune responses. J Exp Med 139:74–92
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847
Damle RN, Temburni S, Calissano C, Yancopoulos S, Banapour T, Sison C, Allen SL, Rai KR, Chiorazzi N (2007) CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood 110:3352–3359
Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916
Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N (1998) Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 102:1515–1525
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA (2010) Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115:2578–2585
Gandhi V (2010) Targeting kinases in CML CLL. Blood 116:1999–2000
Genestier L, Taillardet M, Mondiere P, Gheit H, Bella C, Defrance T (2007) TLR agonists selectively promote terminal plasma cell differentiation of B cell subsets specialized in thymus-independent responses. J Immunol 178:7779–7786
Ghia P, Circosta P, Scielzo C, Vallario A, Camporeale A, Granziero L, Caligaris-Cappio F (2005) Differential effects on CLL cell survival exerted by different microenvironmental elements. Curr Top Microbiol Immunol 294:135–145
Granziero L, Ghia P, Circosta P, Gottardi D, Strola G, Geuna M, Montagna L, Piccoli P, Chilosi M, Caligaris-Cappio F (2001) Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood 97:2777–2783
Guarini A, Chiaretti S, Tavolaro S, Maggio R, Peragine N, Citarella F, Ricciardi MR, Santangelo S, Marinelli M, De Propris MS, Messina M, Mauro FR, Del Giudice I, Foa R (2008) BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells. Blood 112:782–792
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854
Hamblin TJ, Davis ZA, Oscier DG (2008) Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia – long-term follow up of patients with different percentages of mutations. Br J Haematol 140:320–323
Hancer VS, Kose M, Diz-Kucukkaya R, Yavuz AS, Aktan M (2011) Activation-induced cytidine deaminase mRNA levels in chronic lymphocytic leukemia. Leuk Lymphoma 52:79–84
He B, Qiao X, Cerutti A (2004) CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol 173:4479–4491
Herling M, Patel KA, Khalili J, Schlette E, Kobayashi R, Medeiros LJ, Jones D (2006) TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state. Leukemia 20:280–285
Herling M, Patel KA, Weit N, Lilienthal N, Hallek M, Keating MJ, Jones D (2009) High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 114:4675–4686
Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ (2010) Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116:2078–2088
Hu CC, Dougan SK, Winter SV, Paton AW, Paton JC, Ploegh HL (2009) Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes. J Exp Med 206:2429–2440
Jahrsdorfer B, Wooldridge JE, Blackwell SE, Taylor CM, Griffith TS, Link BK, Weiner GJ (2005) Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol 77:378–387
Jones DT, Addison E, North JM, Lowdell MW, Hoffbrand AV, Mehta AB, Ganeshaguru K, Folarin NI, Wickremasinghe RG (2004) Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells’ sensitivity to cytotoxic drugs. Blood 103:1855–1861
Karhu R, Tobin G, Thunberg U, Vilpo L, Sundstrom C, Knuutila S, Rosenquist R, Vilpo J (2003) More extensive genetic alterations in unmutated than in hypermutated cases of chronic lymphocytic leukemia. Genes Chromosom Cancer 37:417–420
Kern C, Cornuel JF, Billard C, Tang R, Rouillard D, Stenou V, Defrance T, Ajchenbaum-Cymbalista F, Simonin PY, Feldblum S, Kolb JP (2004) Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 103:679–688
Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–167
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549
Kriss CL, Pinilla-Ibarz JA, Mailloux AW, Powers JJ, Tang CH, Kang CW, Zanesi N, Epling-Burnette PK, Sotomayor EM, Croce CM, Del Valle JR, Hu CC (2012) Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 120:1027–1038
Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P, Dohner H, Stilgenbauer S (2002) V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416
Lanham S, Hamblin T, Oscier D, Ibbotson R, Stevenson F, Packham G (2003) Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 101:1087–1093
Lapalombella R, Andritsos L, Liu Q, May SE, Browning R, Pham LV, Blum KA, Blum W, Ramanunni A, Raymond CA, Smith LL, Lehman A, Mo X, Jarjoura D, Chen CS, Ford R Jr, Rader C, Muthusamy N, Johnson AJ, Byrd JC (2010) Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway. Blood 115:2619–2629
Longo PG, Laurenti L, Gobessi S, Petlickovski A, Pelosi M, Chiusolo P, Sica S, Leone G, Efremov DG (2007) The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease. Leukemia 21:110–120
Martin S, Hill DS, Paton JC, Paton AW, Birch-Machin MA, Lovat PE, Redfern CP (2010) Targeting GRP78 to enhance melanoma cell death. Pigment Cell Melanoma Res 23:675–682
Meyer-Bahlburg A, Khim S, Rawlings DJ (2007) B cell intrinsic TLR signals amplify but are not required for humoral immunity. J Exp Med 204:3095–3101
Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK (2007) Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 109:4424–4431
Muzio M, Apollonio B, Scielzo C, Frenquelli M, Vandoni I, Boussiotis V, Caligaris-Cappio F, Ghia P (2008) Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood 112:188–195
Novak AJ, Bram RJ, Kay NE, Jelinek DF (2002) Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood 100:2973–2979
Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, Hamblin TJ, Devereux S (2008) CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111:5173–5181
Pekarsky Y, Santanam U, Cimmino A, Palamarchuk A, Efanov A, Maximov V, Volinia S, Alder H, Liu CG, Rassenti L, Calin GA, Hagan JP, Kipps T, Croce CM (2006) Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res 66:11590–11593
Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, Byrd JC, Gribben JG (2008) Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 118:2427–2437
Rosati E, Sabatini R, Rampino G, De Falco F, Di Ianni M, Falzetti F, Fettucciari K, Bartoli A, Screpanti I, Marconi P (2010) Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL. Blood 116:2713–2723
Tsukada N, Burger JA, Zvaifler NJ, Kipps TJ (2002) Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia. Blood 99:1030–1037
Virgilio L, Narducci MG, Isobe M, Billips LG, Cooper MD, Croce CM, Russo G (1994) Identification of the TCL1 gene involved in T-cell malignancies. Proc Natl Acad Sci U S A 91:12530–12534
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Pinilla-Ibarz, J., Hu, CC.A. (2012). Chronic Lymphocytic Leukemia: From Pathobiology to Targeted Therapy. In: Tao, J., Sotomayor, E. (eds) Hematologic Cancers: From Molecular Pathobiology to Targeted Therapeutics. Cancer Growth and Progression, vol 14. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5028-9_3
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DOI: https://doi.org/10.1007/978-94-007-5028-9_3
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