In silico analyses reveal common cellular pathways affected by loss of heterozygosity (LOH) events in the lymphomagenesis of Non-Hodgkin’s lymphoma (NHL)

BMC Genomics

Lyn R Griffiths³  Maher K Gandhi¹  Rod Lea³  Larisa M Haupt³  Emily Camilleri²  Carlos Aya-Bonilla³ 

[1] Centre for Experimental Haematology, Translational Research Institute, Brisbane, Australia;Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA;Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia

关键词: NHL;    Pathway analysis;    Interactome;    PTPRJ;    LOH;   

Others  :  1217207
DOI  :  10.1186/1471-2164-15-390

 received in 2014-01-21, accepted in 2014-05-02,  发布年份 2014

【 摘 要 】

Background

The analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies. Recently, using a high resolution loss of heterozygosity (LOH) analysis, we identified a number of potential tumour suppressor genes (TSGs) within common LOH regions across cases suffering from two of the most common forms of Non-Hodgkin’s lymphoma (NHL), Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). From these studies LOH of the protein tyrosine phosphatase receptor type J (PTPRJ) gene was identified as a common event in the lymphomagenesis of these B-cell lymphomas. The present study aimed to determine the cellular pathways affected by the inactivation of these TSGs including PTPRJ in FL and DLBCL tumourigenesis.

Results

Pathway analytical approaches identified that candidate TSGs located within common LOH regions participate within cellular pathways, which may play a crucial role in FL and DLBCL lymphomagenesis (i.e., metabolic pathways). These analyses also identified genes within the interactome of PTPRJ (i.e. PTPN11 and B2M) that when inactivated in NHL may play an important role in tumourigenesis. We also detected genes that are differentially expressed in cases with and without LOH of PTPRJ, such as NFATC3 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3). Moreover, upregulation of the VEGF, MAPK and ERBB signalling pathways was also observed in NHL cases with LOH of PTPRJ, indicating that LOH-driving events causing inactivation of PTPRJ, apart from possibly inducing a constitutive activation of these pathways by reduction or abrogation of its dephosphorylation activity, may also induce upregulation of these pathways when inactivated. This finding implicates these pathways in the lymphomagenesis and progression of FL and DLBCL.

Conclusions

The evidence obtained in this research supports findings suggesting that FL and DLBCL share common pathogenic mechanisms. Also, it indicates that PTPRJ can play a crucial role in the pathogenesis of these B-cell tumours and suggests that activation of PTPRJ might be an interesting novel chemotherapeutic target for the treatment of these B-cell tumours.

【 授权许可】

   
2014 Aya-Bonilla et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer (IARC); 2008.
• [2]Turner JJ, Morton LM, Linet MS, Clarke CA, Kadin ME, Vajdic CM, Monnereau A, Maynadie M, Chiu BC, Marcos-Gragera R, Costantini AS, Cerhan JR, Weisenburger DD: InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood 2010, 116(20):e90-98.
• [3]Jayasekara H, Karahalios A, Juneja S, Thursfield V, Farrugia H, English DR, Giles GG: Incidence and survival of lymphohematopoietic neoplasms according to the World Health Organization classification: a population-based study from the Victorian Cancer Registry in Australia. Leuk Lymphoma 2010, 51(3):456-468.
• [4]Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'Olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M: R-CVP Versus R-CHOP Versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013, 31:1506-1513.
• [5]Friedberg JW, Fisher RI: Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am 2008, 22(5):941-952. ix
• [6]Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005, 23(18):4117-4126.
• [7]Green MR, Aya-Bonilla C, Gandhi MK, Lea RA, Wellwood J, Wood P, Marlton P, Griffiths LR: Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin’s lymphoma. Genes Chromosomes Cancer 2011, 50(5):313-326.
• [8]Aya-Bonilla C, Green MR, Camilleri E, Benton M, Keane C, Marlton P, Lea R, Gandhi MK, Griffiths LR: High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to non-hodgkin’s lymphoma. Genes Chromosom Cancer 2013, 52(5):467-479.
• [9]Iuliano R, Le Pera I, Cristofaro C, Baudi F, Arturi F, Pallante P, Martelli ML, Trapasso F, Chiariotti L, Fusco A: The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis. Oncogene 2004, 23(52):8432-8438.
• [10]Petermann A, Haase D, Wetzel A, Balavenkatraman KK, Tenev T, Guhrs KH, Friedrich S, Nakamura M, Mawrin C, Bohmer FD: Loss of the protein-tyrosine phosphatase DEP-1/PTPRJ drives meningioma cell motility. Brain Pathol 2011, 21(4):405-418.
• [11]Ruivenkamp C, Hermsen M, Postma C, Klous A, Baak J, Meijer G, Demant P: LOH of PTPRJ occurs early in colorectal cancer and is associated with chromosomal loss of 18q12-21. Oncogene 2003, 22(22):3472-3474.
• [12]Ruivenkamp CA, van Wezel T, Zanon C, Stassen AP, Vlcek C, Csikos T, Klous AM, Tripodis N, Perrakis A, Boerrigter L, Groot PC, Lindeman J, Mooi WJ, Meijjer GA, Scholten G, Dauwerse H, Paces V, van Zandwijk N, van Ommen GJ, Demant P: Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 2002, 31(3):295-300.
• [13]Arora D, Stopp S, Bohmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Ronnstrand L, Tanzer S, Bauer R, Bohmer FD, Muller JP: Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. J Biol Chem 2011, 286(13):10918-10929.
• [14]Baker JE, Majeti R, Tangye SG, Weiss A: Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation. Mol Cell Biol 2001, 21(7):2393-2403.
• [15]Kovalenko M, Denner K, Sandstrom J, Persson C, Gross S, Jandt E, Vilella R, Bohmer F, Ostman A: Site-selective dephosphorylation of the platelet-derived growth factor beta-receptor by the receptor-like protein-tyrosine phosphatase DEP-1. J Biol Chem 2000, 275(21):16219-16226.
• [16]Lampugnani MG, Zanetti A, Corada M, Takahashi T, Balconi G, Breviario F, Orsenigo F, Cattelino A, Kemler R, Daniel TO, Dejana E: Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol 2003, 161(4):793-804.
• [17]Sacco F, Tinti M, Palma A, Ferrari E, Nardozza AP, van Huijsduijnen Hooft R, Takahashi T, Castagnoli L, Cesareni G: Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases. J Biol Chem 2009, 284(33):22048-22058.
• [18]Tsuboi N, Utsunomiya T, Roberts RL, Ito H, Takahashi K, Noda M, Takahashi T: The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J 2008, 413(1):193-200.
• [19]Zhu JW, Brdicka T, Katsumoto TR, Lin J, Weiss A: Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling. Immunity 2008, 28(2):183-196.
• [20]Takahashi K, Mernaugh RL, Friedman DB, Weller R, Tsuboi N, Yamashita H, Quaranta V, Takahashi T: Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc Natl Acad Sci 2012, 109(6):1985-1990.
• [21]Whiteford JR, Xian X, Chaussade C, Vanhaesebroeck B, Nourshargh S, Couchman JR: Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148. Mol Biol Cell 2011, 22(19):3609-3624.
• [22]Ortuso F, Paduano F, Carotenuto A, Gomez-Monterrey I, Bilotta A, Gaudio E, Sala M, Artese A, Vernieri E, Dattilo V, Iuliano R, Brancaccio D, Bertamino A, Musella S, Alcaro S, Grieco P, Perrotti N, Croce CM, Novellino E, Fusco A, Campiglia P, Trapasso F: Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation. ACS Chem Biol 2013, 8(7):1497-1506.
• [23]Paduano F, Dattilo V, Narciso D, Bilotta A, Gaudio E, Menniti M, Agosti V, Palmieri C, Perrotti N, Fusco A, Trapasso F, Iuliano R: Protein tyrosine phosphatase PTPRJ is negatively regulated by microRNA-328. FEBS J 2013, 280(2):401-412.
• [24]Paduano F, Ortuso F, Campiglia P, Raso C, Iaccino E, Gaspari M, Gaudio E, Mangone G, Carotenuto A, Bilotta A, Narciso D, Palmieri C, Agosti V, Artese A, Gomez-Monterrey I, Sala M, Cuda G, Iuliano R, Perrotti N, Scala G, Viglietto G, Alcaro S, Croce CM, Novellino E, Fusco A, Trapasso F: Isolation and functional characterization of peptide agonists of PTPRJ, a tyrosine phosphatase receptor endowed with tumor suppressor activity. ACS Chem Biol 2012, 7(10):1666-1676.
• [25]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144(5):646-674.
• [26]Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324(5930):1029-1033.
• [27]Phang JM, Liu W, Hancock C, Christian KJ: The proline regulatory axis and cancer. Front Oncol 2012, 2:60.
• [28]Catchpole G, Platzer A, Weikert C, Kempkensteffen C, Johannsen M, Krause H, Jung K, Miller K, Willmitzer L, Selbig J, Weikert S: Metabolic profiling reveals key metabolic features of renal cell carcinoma. J Cell Mol Med 2011, 15(1):109-118.
• [29]Wang J, Yuan Y, Zhou Y, Guo L, Zhang L, Kuai X, Deng B, Pan Z, Li D, He F: Protein interaction data set highlighted with human Ras-MAPK/PI3K signaling pathways. J Proteome Res 2008, 7(9):3879-3889.
• [30]Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G, Murty VV, Dominguez-Sola D, Pasqualucci L, Dalla-Favera R: Combined genetic inactivation of beta2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011, 20(6):728-740.
• [31]Hill DM, Kasliwal T, Schwarz E, Hebert AM, Chen T, Gubina E, Zhang L, Kozlowski S: A dominant negative mutant beta 2-microglobulin blocks the extracellular folding of a major histocompatibility complex class I heavy chain. J Biol Chem 2003, 278(8):5630-5638.
• [32]Cunnick JM, Meng S, Ren Y, Desponts C, Wang HG, Djeu JY, Wu J: Regulation of the mitogen-activated protein kinase signaling pathway by SHP2. J Biol Chem 2002, 277(11):9498-9504.
• [33]Qu CK, Nguyen S, Chen J, Feng GS: Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 2001, 97(4):911-914.
• [34]Hugues L, Cave H, Philippe N, Pereira S, Fenaux P, Preudhomme C: Mutations of PTPN11 are rare in adult myeloid malignancies. Haematologica 2005, 90(6):853-854.
• [35]Jongmans MC, van der Burgt I, Hoogerbrugge PM, Noordam K, Yntema HG, Nillesen WM, Kuiper RP, Ligtenberg MJ, van Kessel AG, van Krieken JH, Kiemeney LA, Hoogerbrugge N: Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet 2011, 19(8):870-874.
• [36]Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A: Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 2004, 104(2):307-313.
• [37]Urso K, Alfranca A, Martínez-Martínez S, Escolano A, Ortega I, Rodríguez A, Redondo JM: NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis. Blood 2011, 118(3):795-803.
• [38]Glud SZ, Sorensen AB, Andrulis M, Wang B, Kondo E, Jessen R, Krenacs L, Stelkovics E, Wabl M, Serfling E, Palmetshofer A, Pedersen FS: A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 2005, 106(10):3546-3552.
• [39]Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM: Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 2006, 107(9):3639-3646.
• [40]Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM: Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma. Cancer Res 2006, 66(20):10145-10152.
• [41]Tangye SG, Phillips JH, Lanier LL, de Vries JE, Aversa G: CD148: a receptor-type protein tyrosine phosphatase involved in the regulation of human T cell activation. J Immunol 1998, 161(7):3249-3255.
• [42]Paydas S, Seydaoglu G, Ergin M, Erdogan S, Yavuz S: The prognostic significance of VEGF-C and VEGF-A in non-Hodgkin lymphomas. Leuk Lymphoma 2009, 50(3):366-373.
• [43]Ruan J, Hajjar K, Rafii S, Leonard JP: Angiogenesis and antiangiogenic therapy in non-Hodgkin’s lymphoma. Ann Oncol 2009, 20(3):413-424.
• [44]Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002, 8(1):68-74.
• [45]Takahashi T, Takahashi K, Mernaugh RL, Tsuboi N, Liu H, Daniel TO: A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis. Blood 2006, 108(4):1234-1242.
• [46]Tarcic G, Boguslavsky SK, Wakim J, Kiuchi T, Liu A, Reinitz F, Nathanson D, Takahashi T, Mischel PS, Ng T, Yarden Y: An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr Biol 2009, 19(21):1788-1798.
• [47]de la Fuente-Garcia MA, Nicolas JM, Freed JH, Palou E, Thomas AP, Vilella R, Vives J, Gaya A: CD148 is a membrane protein tyrosine phosphatase present in all hematopoietic lineages and is involved in signal transduction on lymphocytes. Blood 1998, 91(8):2800-2809.
• [48]Toba K, Hanawa H, Sakaue M, Yoshida K, Itoh H, Tsuchiyama J, Maruyama S, Narita M, Takahashi M, Watanabe K, Aizawa Y: Fc epsilon RI and CD22 mRNA are expressed in early B-lineage and myeloid leukemia cell lines. Leuk Res 2003, 27(2):173-182.
• [49]Trapasso F, Iuliano R, Boccia A, Stella A, Visconti R, Bruni P, Baldassarre G, Santoro M, Viglietto G, Fusco A: Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1). Mol Cell Biol 2000, 20(24):9236-9246.
• [50]Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, Miller TP, LeBlanc M, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, et al.: Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004, 351(21):2159-2169.
• [51]Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, et al.: Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008, 359(22):2313-2323.
• [52]Gould J, Getz G, Monti S, Reich M, Mesirov JP: Comparative gene marker selection suite. Bioinformatics 2006, 22(15):1924-1925.