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Chronic Lymphocytic Leukemia pp 51–70Cite as

Chronic Lymphocytic Leukemia: Molecular Genetics and Animal Models

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 294))

Abstract

Chronic lymphocytic leukemia accounts for almost 30% of all adult leukemia cases in the United States and Western Europe. Although several common genomic abnormalities in CLL have been identified, mutational and functional analysis of corresponding genes so far have not proved their involvement in CLL. Our latest studies demonstrated functional involvement of Tcl1 oncoprotein and microRNA genes in the pathogenesis of CLL. Deregulated expressionofTcl1 in transgenic mice resulted in CLL. These CLL tumors showed abnormalities in expression of murine microRNA genes mmu-mir-15a andmmu-mir-16-1. Interestingly, human homologs of these genes, mir-15a and mir-16-1, located at the chromosome 13q14 are also deleted in human CLL samples. In this review we summarize and discuss these new developments. These recently emerged insights into the molecular mechanisms of CLL will allow for the development of new approaches to treat this disease.

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References

  • Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME, Taguchi T, Testa JR, Tsichlis PN (1993) The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 8:1957–1963

    PubMed  CAS  Google Scholar 

  • Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Brito-Babapulle V, Catovsky D (1991) Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia. Cancer Genet Cytogenet 55:1–9

    Article  PubMed  CAS  Google Scholar 

  • Bullrich F, Croce C (2001) Molecular biology of chronic lymphocytic leukemia. In: Bruce Cheson (ed) Chronic lymphocytic leukemias, 2nd edn, revised and expanded. Marcel Dekker, New York, pp 9–32

    Google Scholar 

  • Bullrich F, Fujii H, Calin G, Mabuchi H, Negrini M, Pekarsky Y, Rassenti L, Alder H, Reed JC, Keating MJ, Kipps TJ, Croce CM (2001) Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene. Cancer Res 61:6640–6648

    PubMed  CAS  Google Scholar 

  • Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, Croce CM, Barbanti-Brodano G, Russo G, Negrini M (2000) Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serinethreonine phosphatase 2A in human neoplasms. Oncogene 19:1191–1195

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 99:15524–15529

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell’Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM (2004a) MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci U S A 101:11755–11760

    PubMed  CAS  Google Scholar 

  • Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004b) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101:2999–3004

    PubMed  CAS  Google Scholar 

  • Calnan BJ, Szychowski S, Chan FK, Cado D, Winoto A (1995) A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3:273–282

    PubMed  CAS  Google Scholar 

  • Chan TO, Rittenhouse SE, Tsichlis PN (1999) AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 68:965–1014

    Article  PubMed  CAS  Google Scholar 

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  PubMed  CAS  Google Scholar 

  • Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival inchronic lymphocytic leukemia. N Engl J Med 343:1910–1916

    Article  PubMed  CAS  Google Scholar 

  • Du K, Montminy M (1998) CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273:32377–32379

    PubMed  CAS  Google Scholar 

  • Hallas C, Pekarsky Y, Itoyama T, Varnum J, Bichi R, Rothstein JL, Croce CM (1999) Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes. Proc Natl Acad Sci U S A 96:14418–14423

    Article  PubMed  CAS  Google Scholar 

  • Hammarsund M, Corcoran MM, Wilson W, Zhu C, Einhorn S, Sangfelt O, Grander D (2004) Characterization of a novel B-CLL candidate gene—DLEU7—located in the 13q14 tumor suppressor locus. FEBS Lett 556:75–80

    Article  PubMed  CAS  Google Scholar 

  • Hazel TG, Nathans D, Lau LF (1988) A gene inducible by serumgrowth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A 85:8444–8448

    PubMed  CAS  Google Scholar 

  • Hirata Y, Kiuchi K, Chen HC, Milbrandt J, Guroff G (1993) The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B. J Biol Chem 268:24808–24812

    PubMed  CAS  Google Scholar 

  • Hoyer KK, French SW, Turner DE, Nguyen MT, Renard M, Malone CS, Knoetig S, Qi CF, Su TT, Cheroutre H, Wall R, Rawlings DJ, Morse HC 3rd, Teitell MA (2002) Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma. Proc Natl Acad Sci U S A 99:14392–14397

    Article  PubMed  CAS  Google Scholar 

  • Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838

    Article  PubMed  CAS  Google Scholar 

  • Ivanov DV, Tyazhelova TV, Lemonnier L, Kononenko N, Pestova AA, Nikitin EA, Prevarskaya N, Skryma R, Panchin YV, Yankovsky NK, Baranova AV (2003) A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3. FEBS Lett 539:156–160

    Article  PubMed  CAS  Google Scholar 

  • Kapanadze B, Kashuba V, Baranova A, Rasool O, van Everdink W, Liu Y, Syomov A, Corcoran M, Poltaraus A, Brodyansky V, Syomova N, Kazakov A, Ibbotson R, van den Berg A, Gizatullin R, Fedorova L, Sulimova G, Zelenin A, Deaven L, Lehrach H, Grander D, Buys C, Oscier D, Zabarovsky ER, Yankovsky N (1998) A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukemia and identification of a new putative tumor suppressor gene, Leu5. FEBS Lett 426:266–270

    CAS  Google Scholar 

  • Katagiri Y, Hirata Y, Milbrandt J, Guroff G (1997) Differential regulation of the transcriptional activity of the orphan nuclear receptor NGFI-B by membrane depolarization and nerve growth factor. J Biol Chem 272:31278–31284

    Article  PubMed  CAS  Google Scholar 

  • Kohler M, Ansieau S, Prehn S, Leutz A, Haller H, Hartmann E (1997) Cloning of two novel human importin-alpha subunits and analysis of the expression pattern of the importin-alpha protein family. FEBS Lett 417:104–108

    PubMed  CAS  Google Scholar 

  • Kunstle G, Laine J, Pierron G, Kagami Si S, Nakajima H, Hoh F, Roumestand C, Stern MH, Noguchi M (2002) Identification of Akt association and oligomerization domains of the Akt kinase coactivator TCL1. Mol Cell Biol 22:1513–1525

    Article  PubMed  CAS  Google Scholar 

  • Laine J, Kunstle G, Obata T, Sha M, Noguchi M (2000) The protooncogene TCL1 is an Akt kinase coactivator. Mol Cell 6:395–407

    Article  PubMed  CAS  Google Scholar 

  • Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, Dumitru CD, Shimizu M, Zupo S, Dono M, Alder H, Bullrich F, Negrini M, Croce CM (2004) An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A 101:9740–9744

    PubMed  CAS  Google Scholar 

  • Liu Y, Corcoran M, Rasool O, Ivanova G, Ibbotson R, Grander D, Iyengar A, Baranova A, Kashuba V, Merup M, Wu X, Gardiner A, Mullenbach R, Poltaraus A, Hultstrom AL, Juliusson G, Chapman R, Tiller M, Cotter F, Gahrton G, Yankovsky N, Zabarovsky E, Einhorn S, Oscier D (1997) Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia. Oncogene 15:2463–2473

    Article  PubMed  CAS  Google Scholar 

  • Liu ZG, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA (1994) Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature 367:281–284

    PubMed  CAS  Google Scholar 

  • Mabuchi H, Fujii H, Calin G, Alder H, Negrini M, Rassenti L, Kipps TJ, Bullrich F, Croce CM (2001) Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res 61:2870–2877

    PubMed  CAS  Google Scholar 

  • Madani A, Choukroun V, Soulier J, Cacheux V, Claisse JF, Valensi F, Daliphard S, Cazin B, Levy V, Leblond V, Daniel MT, Sigaux F, Stern MH (1996) Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations. Blood 87:1923–1927

    PubMed  CAS  Google Scholar 

  • Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, Gotoh Y (2001) Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J Biol Chem 276:32799–32805

    Article  PubMed  CAS  Google Scholar 

  • Mertens D, Wolf S, Schroeter P, Schaffner C, Dohner H, Stilgenbauer S, Lichter P (2002) 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

    Article  PubMed  CAS  Google Scholar 

  • Migliazza A, Bosch F, Komatsu H, Cayanis E, Martinotti S, Toniato E, Guccione E, Qu X, Chien M, Murty VV, Gaidano G, Inghirami G, Zhang P, Fischer S, Kalachikov SM, Russo J, Edelman I, Efstratiadis A, Dalla-Favera R (2001) Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia. Blood 97:2098–2104

    Article  PubMed  CAS  Google Scholar 

  • Mok CL, Gil-Gomez G, Williams O, Coles M, Taga S, Tolaini M, Norton T, Kioussis D, Brady HJ (1999) Bad can act as a key regulator of T cell apoptosis and T cell development. J Exp Med 189:575–586

    Article  PubMed  CAS  Google Scholar 

  • Narducci MG, Virgilio L, Isobe M, Stoppacciaro A, Elli R, Fiorilli M, Carbonari M, Antonelli A, Chessa L, Croce CM (1995) TCL1 oncogene activation in preleukemic T cells from a case of ataxia-telangiectasia. Blood 86:2358–2364

    PubMed  CAS  Google Scholar 

  • Narducci MG, Pescarmona E, Lazzeri C, Signoretti S, Lavinia AM, Remotti D, Scala E, Baroni CD, Stoppacciaro A, Croce CM, Russo G (2000) Regulation of TCL1 expression in B-and T-cell lymphomas and reactive lymphoid tissues. Cancer Res 60:2095–2100

    PubMed  CAS  Google Scholar 

  • Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE, Corcoran MM, Chapman RM, Thomas PW, Copplestone JA, Orchard JA, Hamblin TJ (2002)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 100:1177–1184

    PubMed  CAS  Google Scholar 

  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85

    PubMed  CAS  Google Scholar 

  • Paulsen RF, Granas K, Johnsen H, Rolseth V, Sterri S (1995) Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators. J Mol Neurosci 6:249–255

    PubMed  CAS  Google Scholar 

  • Pekarsky Y, Hallas C, Isobe M, Russo G, Croce CM (1999) Abnormalities at 14q32.1 in T cell malignancies involve two oncogenes. Proc Natl Acad Sci U S A 96:2949–2951

    Article  PubMed  CAS  Google Scholar 

  • Pekarsky Y, Koval A, Hallas C, Bichi R, Tresini M, Malstrom S, Russo G, Tsichlis P, Croce CM (2000) Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc Natl Acad Sci U S A 97:3028–3033

    Article  PubMed  CAS  Google Scholar 

  • Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM (2001) Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci U S A 98:3690–3694

    Article  PubMed  CAS  Google Scholar 

  • Planelles L, Carvalho-Pinto CE, Hardenberg G, Smaniotto S, Savino W, Gomez-Caro R, Alvarez-Mon M, de Jong J, Eldering E, Martinez-A C, Medema JP, Hahne M (2004) APRIL promotes B-1 cell-associated neoplasm. Cancer Cell 6:399–408

    Article  PubMed  CAS  Google Scholar 

  • Rondeau G, Moreau I, Bezieau S, Petit JL, Heilig R, Fernandez S, Pennarun E, Myers JS, Batzer MA, Moisan JP, Devilder MC (2001) Comprehensive analysis of a large genomic sequence at the putative B-cell chronic lymphocytic leukaemia (B-CLL) tumour suppresser gene locus. Mutat Res 458:55–70

    PubMed  CAS  Google Scholar 

  • Russo G, Isobe M, Gatti R, Finan J, Batuman O, Huebner K, Nowell PC, Croce CM (1989) Molecular analysis of a t(14;14) translocation in leukemic T-cells of an ataxia telangiectasia patient. Proc Natl Acad Sci U S A 86:602–606

    PubMed  CAS  Google Scholar 

  • Said JW, Hoyer KK, French SW, Rosenfelt L, Garcia-Lloret M, Koh PJ, Cheng TC, Sulur GG, Pinkus GS, Kuehl WM, Rawlings DJ, Wall R, Teitell MA (2001) TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma. Lab Invest 81:555–564

    PubMed  CAS  Google Scholar 

  • Sgambati M, Linet M, Devesa S (2001) Chronic lymphocytic leukemia, epidemiological, familial, and genetic aspects. In: Cheson B (ed) Chronic lymphocytic leukemias, 2nd edn, revised and expanded. Marcel Dekker, New York, pp 33–62

    Google Scholar 

  • Sossey-Alaoui K, Kitamura E, Head K, Cowell JK (2002) Characterization of FAM10A4, a member of the ST13 tumor suppressor gene family that maps to the 13q14.3 region associated with B-Cell leukemia, multiple myeloma, and prostate cancer. Genomics 80:5–7

    Article  PubMed  CAS  Google Scholar 

  • Stern MH, Soulier J, Rosenzwajg M, Nakahara K, Canki-Klain N, Aurias A, Sigaux F, Kirsch IR (1993) MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T cell receptor alpha/delta locus in mature T cell proliferations. Oncogene 8:2475–2483

    PubMed  CAS  Google Scholar 

  • Storz G (2002) An expanding universe of noncoding RNAs. Science 296:1260–1263

    Article  PubMed  CAS  Google Scholar 

  • Teitell M, Damore MA, Sulur GG, Turner DE, Stern MH, Said JW, Denny CT, Wall R (1999) TCL1 oncogene expression in AIDS-related lymphomas and lymphoid tissues. Proc Natl Acad Sci U S A 96:9809–9814

    Article  PubMed  CAS  Google Scholar 

  • Thick J, Metcalfe JA, Mak YF, Beatty D, Minegishi M, Dyer MJ, Lucas G, Taylor AM (1996) Expression of either the TCL1 oncogene, or transcripts from its homologue MTCP1/c6.1B, in leukaemic and non-leukaemic T cells from ataxia telangiectasia patients. Oncogene 12:379–386

    PubMed  CAS  Google Scholar 

  • Virgilio L, Isobe M, Narducci MG, Carotenuto P, Camerini B, Kurosawa N, Abbasar-Rushdi, Croce CM, Russo G (1993) Chromosome walking on the TCL1 locus involved in T-cell neoplasia. Proc Natl Acad Sci U S A 90:9275–9279

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Wolf S, Mertens D, Schaffner C, Korz C, Dohner H, Stilgenbauer S, Lichter P (2001) B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions. Hum Mol Genet 10:1275–1285

    Article  PubMed  CAS  Google Scholar 

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  1. Comprehensive Cancer Center, Ohio State University, 410W. 12th Ave., Columbus, OH, 43210, USA

    C. M. Croce

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  1. Y. Pekarsky
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  2. G. A. Calin
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  3. R. Aqeilan
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  4. C. M. Croce
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Pekarsky, Y., Calin, G.A., Aqeilan, R., Croce, C.M. (2005). Chronic Lymphocytic Leukemia: Molecular Genetics and Animal Models. In: Chronic Lymphocytic Leukemia. Current Topics in Microbiology and Immunology, vol 294. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29933-5_4

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