Monday, 9th December 2019

Genetics susceptibility in complex diseases: genes involved in susceptibility to T-cell lymphoblastic lymphoma



José Fernández Piqueras




Research summary:

In the last five years we have been working on murine T-cell lymphoblastic lymphomas (T-LBLs) arising spontaneously in knockout mice and, in particular, with T-LBLs induced by gamma-irradiation in susceptible and resistant inbred strains, as well as in consomics and congenic derived strains.Results obtained in mouse are confirmed in human cell lines derived from this type of lymphomas and in primary T-LBLs.


Abnormal spectral karyotype of a murine T-LBL

Genome wide analyses using cDNA-expression arrays, CGH-arrays and epigenetic approaches, allowed us to identify multiple coding and non-coding (miRNAs) loci underlying genetic susceptibility in these lymphomas. Interestingly, some of these gene alterations occur exclusively in the stroma that accompanies lymphoma cells (ANXA1 and CD274). Other major achievements include the demonstration that down-regulation of specific miRNAs may explain the over-expression of critical oncogenes (as c-MYC, ABL1, BCR-ABL and SMO), and that several tumour suppressor genes (in particular CDKN2A, CDKN2B, and EPHA7) are silenced by the combinatory effect of deletion on one allele and the epigenetic inactivation of the other one








Transcriptional miRNA profiling of murine T-LBLs

------ Genome-wide analysis of copy-number variations (aCGH) and critical coding and non-coding genes involved in  murine T-LBL development ------ Methylation analysis of CpG-islands at the promoter region of EPHA7 gene in human T-LBL samples. MSP and Bisulphite-sequencing.

Over this time, we have registered three patents. Present and future initiatives of our group are (1) to assess the oncogenic potential of over-expression of critical oncogenes exhibiting very low rates of mutations using adoptive transfer approaches with different types of genetically-modified hematopoietic-stem cells, (2) to identify the genetic and epigenetic changes associated with the different stages of T-LBL development (3) to unravel how the deregulation of Fas apoptotic signalling is contributing to T-LBL development (4) to exploit the collateral damage of common deletions to kill lymphoma cells,  and (5) to integrate the results of all genomic approaches into a map of genetic and epigenetic alterations for human T-LBLs  in order to improve prognosis and diagnosis, and to design more effective therapies.

Relevant publications:

  • Bueno MJ, Gómez de Cedrón M, Pérez de Castro I, Gómez-López G, Di Lisio L, Montes Moreno S, Martínez N, Guerrero M, Sánchez-Martínez R, Santos J, Pisano, DG, Piris MA, Fernández-Piqueras J and Malumbres M (2011) Combinatorial effects of microRNAs to suppress the Myc oncogenic pathway. Blood 117(23): 6255-66.
  • Bueno MJ, Gómez de Cedrón M, Laresgoiti U, Fernández-Piqueras J, Zubiaga A and Malumbres M (2010) Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signalling. Molecular Cellular Biology 30 (12): 2983-2995.
  • Santos J, González-Sánchez L, Matabuena-de Yzaguirre M, Villa-Morales M, Cozar P, López-Nieva P, Fernández-Navarro P, Fresno M, Díaz MD, Guenet JL, Montagutelli X & Fernández-Piqueras J. (2009) A role for stroma-derived Annexin A1 as mediator in the control of genetic susceptibility to T-cell lymphoblastic malignancies through PGE2 secretion. Cancer Res 69(6): 2577-87.
  • Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernandez-Piqueras J, Malumbres M (2008) Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell, 13: 496-506.
  • Villa-Morales M, Santos J, Pérez-Gómez E, Quintanilla M and Fernández-Piqueras J (2007) A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas. Cancer Res 67 (11): 5107-5116.

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