High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle

Oncotarget

Volumn 5, Issue 13, 2014, Pages 4694-4708

  Caraballo, Juan M ^a   Acosta, Juan C ^a,g   Cortés, Miguel A ^b   Albajar, Marta ^c   Teresa Gomez Casares M ^d   Batlle López, Ana ^c   Cuadrado, M Angeles ^c   Onaindia, Arantza ^c   Bretones, Gabriel ^a   Llorca, Javier ^a,e   Piris, Miguel A ^c   Colomer, Dolors ^f   León, Javier ^a  

^a UNIVERSITY OF CANTABRIA   (Spain)

^b HOSPITAL DE LAREDO   (Spain)

^c HOSPITAL UNIVERSITARIO MARQUÉS DE VALDECILLA   (Spain)

^d HOSPITAL UNIVERSITARIO DE GRAN CANARIA DR NEGRÍN   (Spain)

^e CIBER EPIDEMIOLOGÍA Y SALUD PÚBLICA CIBERESP   (Spain)

^f HOSPITAL CLÍNIC   (Spain)

^g UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

Chronic lymphocytic leukemia; Fludarabine; Myc; p27; Skp2

Indexed keywords

CD38 ANTIGEN; CYCLIN A; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR 1B; CYCLINE; FLUDARABINE; MESSENGER RNA; MYC PROTEIN; ONCOPROTEIN; PROTEIN BCL 2; PROTEIN KINASE ZAP 70; S PHASE KINASE ASSOCIATED PROTEIN 2; PROTEIN C MYB; S PHASE KINASE ASSOCIATED PROTEIN; TUMOR MARKER;

APOPTOSIS; ARTICLE; B LYMPHOCYTE; CANCER GROWTH; CELL CYCLE; CELL DEATH; CELL VIABILITY; CHRONIC LYMPHATIC LEUKEMIA; CONTROLLED STUDY; DENSITOMETRY; DOWN REGULATION; EXPRESSION VECTOR; FEMALE; GENE DELETION; HUMAN; HUMAN CELL; IMMUNOBLOTTING; IMMUNOFLUORESCENCE TEST; IMMUNOHISTOCHEMISTRY; LEUKEMIA CELL LINE; MAJOR CLINICAL STUDY; MALE; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; PROTEIN TARGETING; REAL TIME POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; UPREGULATION; ADULT; AGED; DRUG RESISTANCE; FLUORESCENCE MICROSCOPY; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MIDDLE AGED; PATHOLOGY; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; TUMOR CELL LINE; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; APOPTOSIS; CELL CYCLE; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASE INHIBITOR P27; CYCLINS; DRUG RESISTANCE, NEOPLASM; FEMALE; GENE EXPRESSION REGULATION, LEUKEMIC; HUMANS; IMMUNOBLOTTING; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MALE; MICROSCOPY, FLUORESCENCE; MIDDLE AGED; PROTO-ONCOGENE PROTEINS C-MYB; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; S-PHASE KINASE-ASSOCIATED PROTEINS; TUMOR MARKERS, BIOLOGICAL;

EID: 84905027833     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.2100     Document Type: Article

References (67)

1. Chiorazzi N, Rai KR and Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352:804-815.
2. Bertilaccio MT, Scielzo C, Muzio M and Caligaris-Cappio F. An overview of chronic lymphocytic leukaemia biology. Best Pract Res Clin Haematol. 2010; 23:21-32.
3. Zenz T, Mertens D, Kuppers R, Dohner H and Stilgenbauer S. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010; 10:37-50.
4. Decker T, Hipp S, Hahntow I, Schneller F and Peschel C. Expression of cyclin E in resting and activated B-chronic lymphocytic leukaemia cells: cyclin E/cdk2 as a potential therapeutic target. Br J Haematol. 2004; 125:141-148.
5. Sanhes L, Tang R, Delmer A, DeCaprio JA and Ajchenbaum-Cymbalista F. Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases. Leukemia. 2003; 17:1104-1111.
6. Vrhovac R, Delmer A, Tang R, Marie JP, Zittoun R and Ajchenbaum-Cymbalista F. Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia. Blood. 1998; 91:4694-4700.
7. Wolowiec D, Wojtowicz M, Ciszak L, Kosmaczewska A, Frydecka I, Potoczek S, Urbaniak-Kujda D, Kapelko-Slowik K and Kuliczkowski K. High intracellular content of cyclin-dependent kinase inhibitor p27(Kip1) in early-and intermediate stage B-cell chronic lymphocytic leukemia lymphocytes predicts rapid progression of the disease. Eur J Haematol. 2009; 82:260-266.
8. Frenquelli M, Muzio M, Scielzo C, Fazi C, Scarfo L, Rossi C, Ferrari G, Ghia P and Caligaris-Cappio F. MicroRNA and proliferation control in chronic lymphocytic leukemia: functional relationship between miR-221/222 cluster and p27. Blood. 2010; 115:3949-3959.
9. Chu IM, Hengst L and Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008; 8:253-267.
10. Slingerland J and Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 2000; 183:10-17.
11. Philipp-Staheli J, Payne SR and Kemp CJ. p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res. 2001; 264:148-168.
12. Carrano AC, Eytan E, Hershko A and Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999; 1:193-199.
13. Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U and Krek W. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999; 1:207-214.
14. Tsvetkov LM, Yeh KH, Lee SJ, Sun H and Zhang H p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol. 1999; 9:661-664.
15. Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT, Ooi HS, Orlov YL, Shahab A, Yong HC, Fu Y, Weng Z, Kuznetsov VA, Sung WK, Ruan Y and Dang CV. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci U S A. 2006; 103:17834-17839.
16. McMahon SB. Emerging Concepts in the Analysis of Transcriptional Targets of the MYC Oncoprotein: Are the Targets Targetable?. Genes Cancer. 2010; 1:560-567.
17. Lutz W, Leon J and Eilers M. Contributions of Myc to tumorigenesis. Biochim Biophys Acta. 2002; 1602:61-71.
18. Meyer N and Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008; 8:976-990.
19. Eilers M and Eisenman RN. Myc's broad reach. Genes Dev. 2008; 22:2755-2766.
20. Leon J, Ferrandiz N, Acosta JC and Delgado MD. Inhibition of cell differentiation: A critical mechanism for MYC-mediated carcinogenesis?. Cell Cycle. 2009; 8:1148-1157.
21. Dang CV. MYC on the path to cancer. Cell. 2012; 149:22-35.
22. Conacci-Sorrell M, McFerrin L and Eisenman RN. An Overview of MYC and Its Interactome. Cold Spring Harb Perspect Med. 2014; 4:1-24.
23. Vita MwHenriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. 2006; 16:318-330.
24. Sanchez-Beato M, Sanchez-Aguilera A and Piris MA. Cell cycle deregulation in B-cell lymphomas. Blood. 2003; 101:1220-1235.
25. Delgado MD and Leon J. Myc roles in hematopoiesis and leukemia. Genes Cancer. 2010; 1:605-616.
26. Korz C, Pscherer A, Benner A, Mertens D, Schaffner C, Leupolt E, Dohner H, Stilgenbauer S and Lichter P. Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Blood. 2002; 99:4554-4561.
27. Halina A, Artur P, Barbara MK, Joanna S and Anna D. Alterations in TP53, cyclin D2, c-Myc, p21WAF1/CIP1 and p27KIP1 expression associated with progression in B-CLL. Folia Histochem Cytobiol. 2010; 48:534-541.
28. Zhang W, Kater AP, Widhopf GF 2nd, Chuang HY, Enzler T, James DF, Poustovoitov M, Tseng PH, Janz S, Hoh C, Herschman H, Karin M and Kipps TJ. B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2010; 107:18956-18960.
29. Rinaldi A, Mian M, Kwee I, Rossi D, Deambrogi C, Mensah AA, Forconi F, Spina V, Cencini E, Drandi D, Ladetto M, Santachiara R, Marasca R, Gattei V, Cavalli F and Zucca E. Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia. Br J Haematol. 2011; 154:590-599.
30. Huh YO, Lin KI, Vega F, Schlette E, Yin CC, Keating MJ, Luthra R, Medeiros LJ and Abruzzo LV. MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis. Br J Haematol. 2008; 142:36-44.
31. Put N, Van Roosbroeck K, Konings P, Meeus P, Brusselmans C, Rack K, Gervais C, Nguyen-Khac F, Chapiro E, Radford-Weiss I, Struski S, Dastugue N, Gachard N, Lefebvre C, Barin C and Eclache V. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course. Ann Hematol. 2012; 91:863-873.
32. Scandurra M, Rossi D, Deambrogi C, Rancoita PM, Chigrinova E, Mian M, Cerri M, Rasi S, Sozzi E, Forconi F, Ponzoni M, Moreno SM, Piris MA, Inghirami G, Zucca E and Gattei V. Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas. Hematol Oncol. 2010; 28:62-67.
33. Rossi D. Myc Addiction in Chronic Lymphocytic Leukemia. Leuk Lymphoma. 2013; 54:905-906.
34. Monti S, Deambrogi C, Rinaldi A, Bertoni F, Gaidano G and Rossi D. MYC network mutations in high-risk chronic lymphocytic leukaemia. Hematol Oncol. 2014; DOI: 10.1002/hon.2117.
35. Chandramohan V, Mineva ND, Burke B, Jeay S, Wu M, Shen J, Yang W, Hann SR and Sonenshein GE. c- Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor. J Cell Biochem. 2008; 104:2091-2106.
36. Kim JW, Mori S and Nevins JR. Myc-induced microRNAs integrate Myc-mediated cell proliferation and cell fate. Cancer Res. 2010; 70:4820-4828.
37. Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J and Eilers M. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J. 1999; 18:5321-5333.
38. Perez-Roger I, Solomon DL, Sewing A and Land H. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27(Kip1) binding to newly formed complexes. Oncogene. 1997; 14:2373-2381.
39. Vlach J, Hennecke S, Alevizopoulos K, Conti D and Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. Embo J. 1996; 15: 6595-6604.
40. Acosta JC, Ferrandiz N, Bretones G, Torrano V, Blanco R, Richard C, O'Connell B, Sedivy J, Delgado MD and Leon J. Myc inhibits p27-induced erythroid differentiation of leukemia cells by repressing erythroid master genes without reversing p27-mediated cell cycle arrest. Mol Cell Biol. 2008; 28:7286-7295.
41. Bretones G, Acosta JC, Caraballo JM, Ferrandiz N, Gomez-Casares MT, Albajar M, Blanco R, Ruiz P, Hung WC, Albero MP, Perez-Roger I and Leon J. SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells. J Biol Chem. 2011; 286:9815-9825.
42. Kitagawa K, Kotake Y and Kitagawa M. Ubiquitin-mediated control of oncogene and tumor suppressor gene products. Cancer Sci. 2009; 100:1374-1381.
43. Kossatz U, Dietrich N, Zender L, Buer J, Manns MP and Malek NP. Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Genes Dev. 2004; 18:2602-2607.
44. Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J and Krek W. Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001; 98:5043-5048.
45. Munoz-Alonso MJ, Acosta JC, Richard C, Delgado MD, Sedivy J and Leon J. p21Cip1 and p27Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J Biol Chem. 2005; 280:18120-18129.
46. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E and Slingerland JM. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002; 8:1153-1160.
47. Rosen DG, Yang G, Cai KQ, Bast RC Jr, Gershenson DM, Silva EG and Liu J. Subcellular localization of p27kip1 expression predicts poor prognosis in human ovarian cancer. Clin Cancer Res. 2005; 11:632-637.
48. Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A and Santoro M. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002; 8:1136-1144.
49. Caligaris-Cappio F and Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?. J Clin Oncol. 2008; 26:4497-4503.
50. Lanasa MC. Novel insights into the biology of CLL. Hematology Am Soc Hematol Educ Program. 2010; 2010:70-76.
51. Billard C. Apoptosis inducers in chronic lymphocytic leukemia. Oncotarget. 2014; 5:309-325.
52. Ghia P, Ferreri AM and Caligaris-Cappio F. Chronic lymphocytic leukemia. Crit Rev Oncol Hematol. 2007; 64:234-246.
53. Wierda WG and O'Brien SM. Initial therapy for patients with chronic lymphocytic leukemia. Semin Oncol. 2006; 33:202-209.
54. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH and Humerickhouse R. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012; 30:488-496.
55. Karan-Djurasevic T, Palibrk V, Zukic B, Spasovski V, Glumac I, Colovic M, Colovic N, Jurisic V, Scorilas A, Pavlovic S and Tosic N. Expression of Bcl2L12 in chronic lymphocytic leukemia patients: association with clinical and molecular prognostic markers. Med Oncol. 2013; 30:405.
56. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, Anile C, Maira G, Mercatelli N, Ciafre SA, Farace MG and Agami R. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007; 26:3699-3708.
57. Cho S, Kim JH, Back SH and Jang SK. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase. Mol Cell Biol. 2005; 25:1283-1297.
58. Alessandrini A, Chiaur DS and Pagano M. Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. Leukemia. 1997; 11:342-345.
59. Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, De Vos J, Hernandez JM, Hofmann WK, Mills KI, Gilkes A, Chiaretti S, ShurtleffSA, Kipps TJ, Rassenti LZ and Yeoh AE. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010; 28:2529-2537.
60. Haslinger C, Schweifer N, Stilgenbauer S, Dohner H, Lichter P, Kraut N, Stratowa C and Abseher R. Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status. J Clin Oncol. 2004; 22:3937-3949.
61. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr and Lu L. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403:503-511.
62. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle. 2004; 3:1133-1137.
63. Hann SR. Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Semin Cancer Biol. 2006; 16:288-302.
64. Vervoorts J, Luscher-FirzlaffJ and Luscher B. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem. 2006; 281:34725-34729.
65. Stacchini A, Aragno M, Vallario A, Alfarano A, Circosta P, Gottardi D, Faldella A, Rege-Cambrin G, Thunberg U, Nilsson K and Caligaris-Cappio F. MEC1 and MEC2: two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. Leuk Res. 1999; 23:127-136.
66. Delgado MD, Lerga A, Canelles M, Gomez-Casares MT and Leon J. Differential regulation of Max and role of c- Myc during erythroid and myelomonocytic differentiation of K562 cells. Oncogene. 1995; 10:1659-1665.
67. Vlach J, Hennecke S and Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J. 1997; 16:5334-5344.