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.
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.
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.