Inicio de sesión

Contact:

Dr. Javier León

Phone: (+34) 942 201952 / Fax : (+34) 942 266399

Email: leonj@unican.es

Mailing address: IBBTEC.

C/ Albert Einstein 22 (PCTCAN)

39011 Santander


Dra. Dolores Delgado

Phone: (+34) 942 201998 / Fax : (+34) 942 266399

Email: delgadmd@unican.es

Mailing address: IBBTEC.
C/ Albert Einstein 22 (PCTCAN)
39011 Santander​





Transcriptional Control in Cancer Cells and Stem Cells

Grupo-Leon-y-Delgado.jpg


Principal Investigators

Javier León, Full Professor

M. Dolores Delgado, Full Professor


Personnel

  • Ana Batlle López, postdoctoral
  • María Gabriela Cortiguera Ruiz, predoctoral
  • Lorena García-Gaipo, predoctoral
  • Lucía García, predoctoral
  • Judit Liaño, predoctoral
  • Ester Molina, predoctoral
  • Rosa Blanco, technician


Research lines and interests

  • Roles of Myc and Myc network proteins Mxd1 and Mnt on cell proliferation and differentiation of hematopoietic and embryonic stem cells
  • Functional interactions of Myc with cell cycle regulatory proteins
  • Myc target genes in leukemia/lymphoma
  • Function of CTCF in the hematopoietic differentiation. We aim to explore the function of CTCF in hematopoietic differentiation through the analysis of their target genes, using cell lines and primary cells. The methodology includes DNA interaction analysis , epigenetic regulation assays, modulation expression, profiling analysis, etc.
  • To know the CTCF involvement in hematological malignancies, especially in lymphomas. We use lymphoma cell lines and samples from patients. The aim is to determine if CTCF could be marker for diagnosis or prognosis in hematological neoplasias


Funding

  • Oncoproteínas MYC Y CTCF en el control transcripcional de la diferenciación hematopoyética y en linfoma. SAF2014-53526R. CoIPs: Javier León y M. Dolores Delgado
  • Función de los reguladores transcripcionales CTCF y CTCF-L (BORIS) en la diferenciación hematopoyética normal y patológica. Instituto de Salud Carlos III. FIS11/00397
  • Terapia epigenética en linfomas de células B. Papel de los reguladores de cromatina de la familia CTCF. Entidad financiadora: Celgene S.L.U.

  • "Red Temática Investigación Cooperativa de Investigación en Cáncer" ISCIII-RETIC RD12/0036/0033. IP: Piero Crespo


Publications (last 10 years)

  • Garcia-Alegría E, Lafita-Navarro MC, Aguado R, Garcia-Gutierrez L, Sarnataro K, Ruiz-Herguido C, Martín F, Bigas A, Canelles M, León J. NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.
    Cancer Lett. 2016 Mar 2. pii: S0304-3835(16)30105-7. doi: 10.1016/j.canlet.2016.02.037. [PubMed]

  • Cortiguera MG, Batlle-López A, Albajar M, Delgado MD, León J. MYC as therapeutical target in leukemia and lymphoma.
    Blood and Lymphatic Cancer: Targets and Therapy 2015:5 75–91.
  • Batlle-López A, Cortiguera MG, Delgado MD. The epigenetic regulator CTCF modulates BCL6 in lymphoma.
    ONCOSCIENCE 2015. 2 (10): 783-784 (Editorial). [PubMed]
  • Batlle-López A, Cortiguera MG, Rosa-Garrido M, Blanco R, Del Cerro E, Torrano V, Wagner SD, Delgado MD. Novel CTCF binding at a site in exon1A of BCL6 is associated with active histone marks and a transcriptionally active locus.
    Oncogene. 2015 Jan 8;34(2):246-56. doi: 10.1038/onc.2013.535. [PubMed]
  • Pérez-Rodríguez A, Batlle-López A, Blanco R, Varela I, León J, Delgado MD, Lourés E, Rodríguez-Trillo A, García-Rivero A, Costa-Pinto J, Batlle J, López-Fernández MF. A novel mutation in ADAMTS13 of a child with Upshaw-Schulman Syndrome.
    Thromb Haemost
    . 2014 Nov;112(5):1065-8. doi: 10.1160/TH14-02-0116. [PubMed]
  • Garcia-Sanz P, Quintanilla A, Lafita MC, Moreno-Bueno G, García-Gutierrez L, Tabor V, Varela I, Shiio Y, Larsson LG, Portillo F, Leon J. Sin3b interacts with myc and decreases myc levels.
    J Biol Chem
    . 2014 Aug 8;289(32):22221-36. doi: 10.1074/jbc.M113.538744. [PubMed]

  • Bretones G, Delgado MD, León J. Myc and cell cycle control.
    Biochim Biophys Acta
    . 2014 Apr 1. pii: S1874-9399(14)00073-X. doi: 10.1016/j.bbagrm.2014.03.013. [PubMed]
  • Caraballo JM, Acosta JC, Cortés MA, Albajar M, Gómez-Casares MT, Batlle-López A, Cuadrado MA, Onaindia A, Bretones G, Llorca J, Piris MA, Colomer D, León J. 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
    . 2014 Jul 15;5(13):4694-708. [PubMed]
  • Delgado, M.D., Albajar, M., Gomez-Casares, M.T., Batlle, A., and León, J. MYC oncogene in myeloid neoplasias.
    Clin Trans Oncol, 15: 87-94  (2013) .PMID: 22911553.[PubMed]
  • Gómez-Casares, M.T. García-Alegria, E., López-Jorge, C.E., Ferrándiz, N., Blanco, R., Alvarez, S., Vaqué, J.P., , Bretones, G., Caraballo, J.M., Sanchez-Bailón, P., Delgado, M.D., Martin-Perez, J., Cigudosa, J.C., and León, J.  MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through down-regulation of p27KIP1 .
    Oncogene 32:2239- 2246 (2012). [PubMed]
  • Grande L, Bretones G, Rosa-Garrido M, Garrido-Martin EM, Hernandez T, FraileS, Botella L, de Alava E, Vidal A, Garcia del Muro X, Villanueva A, Delgado MD,Fernandez-Luna JL. Transcription factors Sp1 and p73 control the expression ofthe proapoptotic protein NOXA in the response of testicular embryonal carcinomacells to cisplatin.
    Journal of Biological Chemistry. 2012 Aug 3;287(32):26495-505. [PubMed]
  • Rosa-Garrido M, Ceballos L, Alonso-Lecue P, Abraira C, Delgado MD, Gandarillas A. A cell cycle role for the epigenetic factor CTCF-L/BORIS. PLoS One.2012;7(6):e39371. [PubMed]
  • Sleutels F, Soochit W, Bartkuhn M, Heath H, Dienstbach S, Bergmaier P, FrankeV, Rosa-Garrido M, van de Nobelen S, Caesar L, van der Reijden M, Bryne JC, vanIjcken W, Grootegoed JA, Delgado MD, Lenhard B, Renkawitz R, Grosveld F, Galjart N. The male germ cell gene regulator CTCFL is functionally different from CTCFand binds CTCF-like consensus sites in a nucleosome composition-dependent manner.
    EPIGENETICS & CHROMATIN 2012 Jun 18;5(1):8. [PubMed]
  • Ferrándiz N, Caraballo JM, García-Gutierrez L, Devgan V, Rodriguez-Paredes M, Lafita MC, Bretones G, Quintanilla A, Muñoz-Alonso MJ, Blanco R, Reyes JC, Agell N, Delgado MD, Dotto GP, León J. p21 as a transcriptional co-repressor of S-phaseand mitotic control genes.
    PLoS One. 2012;7(5):e37759. [PubMed]
  • Muñoz-Alonso MJ, Ceballos L, Bretones G, Frade P, León J, Gandarillas A. MYC accelerates p21(CIP) -induced megakaryocytic differentiation involving early mitosis arrest in leukemia cells.
    J Cell Physiol. 227: 2069–2078 (2012). [PubMed]
  • Albajar, M., Gómez-Casares, M.T., Llorca, J., Mauleon, J., Vaqué, J.P., Acosta, J.C., Bermúdez, A., Donato, N., Delgado, M.D. and León, J.   MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib. Mol Cancer Res 9: 564-576 (2011).
  • Bretones, G., Acosta J.C:, Caraballo, J., Ferrandiz, N., Gómez-Casares, M.T., Albajar, M., Blanco, R., Ruiz, P., Hung, W-C., Albero, M.P., Perez-Roger, I. and León J. Skp2 oncogene is a direct Myc target gene and Myc downregulates p27kip1 through Skp2 in human leukemia cells. J Biol Chem.  286: 9815-25 (2011).
  • Delgado, M.D and León, J. Myc roles in hematopoiesis and leukemia. Genes &Cancer (2010) 1: 605–616. Review
  • Ferrandiz, N, Caraballo, J. M., Albajar, M, Gomez-Casares, M.T., López-Jorge, C.E., Blanco, R., Delgado, M.D. and Leon, J. p21Cip1 confers resistance to imatinib in human chronic myeloid leukemia cells. Cancer Lett 292: 133-139 (2010).
  • Van de Nobelen, S., Rosa-Garrido, M., Leers, J., Heath, H., Soochit, W., Joosen, L., Jonkers, I., Demmers, J., Van der Reijden, M., Torrano, V., Grosveld, F., Delgado, M.D., Renkawitz, R., ,Galjart, N..and Sleutels, F. “CTCF regulates the local epigenetic state of ribosomal DNA repeats”. Epigenetics & Chromatin 3:19 (2010).
  • León J, Ferrándiz, N, Acosta, JC, Delgado, MD. Inhibition of cell differentiation: a critical mechanism for MYC-mediated carcinogenesis? Cell Cycle 8: 1148-1157 (2009)
  • Marques-Garcia F, Ferrandiz N, Fernandez-Alonso R, Gonzalez-Cano L, Herreros-Villanueva M, Rosa-Garrido M, Fernandez-Garcia B, Vaque JP, Marques MM, Alonso ME, Segovia JC, Leon J, Marin MC. p73 plays a role in erythroid differentiation through GATA1 induction. J Biol Chem. 284: 21139-21156 (2009)
  • Ferrandiz, N., Martin-Perez, J., Blanco, R, Donertas, D, Weber, A, Eilers, M, Dotto, P, Delgado, M.D. and Leon, J. HCT116 cells deficient in p21Waf1 are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53. DNA Repair 8: 390-399 (2009).
  • López C, Ajenjo N, Muñoz-Alonso MJ, Frade P, León J, Gómez-Cimiano J. Determination of viability of human cartilage allografts by a rapid and quantitative method not requiring cartilage digestion. Cell Transplant. 17:859-64 (2008).
  • Acosta, J. C., Ferrándiz, N., Bretones, G., Blanco.,R., Torrano, V., Richard,C., O'Conell, B., Sedivy, J., Delgado, M.D.,  León, J. Myc inhibits p27-induced erythroid differentiation of leukemia cells by repressing erythroid master genes without reversing the p27-mediated cell cycle arrest. Mol Cell Biol 28: 7286-7295 (2008).
  • Parreño,M., Casanova, I.,Céspedes, M.V., Vaqué, J.P.,Pavón,M.A., Leon, J. and Mangues, R.Bobel-24 and derivatives induce caspase-Independent Death in Pancreatic Cancer, regardless of Apoptotic Resistance. Cancer Res 68:6313-23 (2008).
  • Albajar, M. Gutierrez, P.,  Richard, C., Rosa-Garrido, M., Gómez-Casares, M.T., Steegmann, J.L. León, J. and Delgado M. D. PU.1 expression is restored upon treatment of chronic myeloid leukemia patients. Cancer Lett 270, 328-336 (2008).
  • Vaqué, JP., Fernández-García, B, García-Sanz, P., Ferrandiz, N., Bretones, G., Calvo, F., Crespo, P., Marín, M.C. and León, J. C-Myc inhibits Ras-mediated differentiation of pheochromocytoma cells by blocking c-Jun up-regulation. Mol Cancer Res. 6:325-339 (2008).
  • Renaud, S; Pugacheva, E; Delgado, M. D; Braunschweig, R; Abdullaev, Z; Loukinov, D Benhattar, J; Lobanenkov, V. Expression of the CTCF-paralogous Cancer-Testis Gene, Brother Of the Regulator of Imprinted Sites (BORIS), Is Regulated by Three Alternative Promoters Modulated by CpG-methylation and by CTCF and p53 Transcription Factors. Nuc Acids Res 35: 7372–7388 (2007).
  • Fernandez-Garcia, B., Vaqué, J.P., Herreros-Villanueva, M., F Marques-Garcia1, Castrillo, F., Fernandez-Medarde, A.,  León, J. and Marín, M.C. p73 cooperates with Ras in the activation of MAP kinase signaling cascade. Cell Death Diff. 14:254-265 (2007).
  • Delgado, M.D. and León, J. "Gene expression regulation and cancer". Clinical & Translational Oncology 8:780-787 (2006).
  • Parreño, M., Vaqué, J.P., Casanova, I., Frade, P, Céspedes, M.V., Pavón, M.A., Molins, A., Camacho, M.,  Vila, L.,  Nomdedeu, J.F.,  Mangues, R., and León, J. Novel triiodo-phenol derivatives induce caspase-independent mitochondrial cell death in leukemia cells which is inhibited by Myc. Mol. Cancer Ther. 5:1166-1175 (2006).
  • Torrano, V., Navascués, J., Docquier,F., Zhang, R., Burke, L., Chernukhin,I., Farrar, D., León, J., Berciano, M.T., Renkawitz, R., Klenova, E., Lafarga, M. and Delgado, M.D.  Targeting of CTCF to the nucleolus inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism. J. Cell Science. 119:1746-1759 (2006).
  • D'Arcy V, Abdullaev ZK, Pore N, Docquier F, Torrano V, Chernukhin I, Smart M, Farrar D, Metodiev M, Fernandez N, Richard C, Delgado MD, Lobanenkov V, Klenova E. The potential of BORIS detected in the leukocytes of breast cancer patients as an early marker of tumorigenesis. Clinical Cancer Research 12 (20): 5978-5986 (1996).
  • Torrano,V.,Chernukhin, I., Docquier, F., D'Arcy, V., Leon, J., Klenova, E., and Delgado, M.D. CTCF regulates growth and erythroid differentiation of human myeloid leukemia cells. J.Biol. Chem. 280: 28152-28161 (2005).
  • Ceballos, E., Muñoz-Alonso, M.J., Berwanger, B, Acosta, J.C., Hernández, R., Krause, M., Hartman, O., Eilers, M. and León, J. Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and up-regulation of  chaperone genes. Oncogene 24: 4559-4571 (2005).
  • Muñoz-Alonso, M.J., Acosta, J.C., Richard, C., Delgado, M.D., Sedivy, J. and LeónJ. p21cip1 and p27kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J.  Biol. Chem. 280: 18120-18129 (2005).
  • Vaqué, J.P., Navascués, J., Shiio, Y., Laiho, M., Ajenjo, N., Mauleon, I., Matallanas, D., Crespo, P. and León, J. Myc antagonizes Ras-mediated growth arrest in leukemia cells through the inhibition of the Ras-Erk-p21Cip1 pathway. J.Biol. Chem. 280: 1112-1122 (2005).