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Study of primary V(D)J induced MYC locus translocations involved in Lymphomagenesis

Project code: PN-III-P4-ID-PCE-2016-0502

Project no.: 178

Project acronym: V(D)JMYC

Field: LS6_6 - Immunogenetics

DNA double stranded breakes(DSB) physiologically occur at various stages during B lymphocyte development at the Immunoglobulin(IG) chromosomal loci. When DSBs at IG loci are coupled with other accidental DNA lesions somewhere else in the genome the concurrent set of events lead to reciprocal translocations, which are exchanges of encoding DNA segments between two distinct non-homologous chromosomes. Although for B cells these translocations are recognized hallmarks of their malignant transformation it is unknown if they are the cause, or if their presence just favors lymphomagenesis(the process of oncogenic degeneration of the lymphoid cell lines). Our project addresses this essential question in oncology trying to capture in time the exact moment when a given induced translocation(MYC/IG) abruptly changes the phenotype of B cells undergoing differentiation. We will use an innovative approach to target MYC locus(chr.8) for DSBs by irradiation. With it, we will induce translocations between an IG and MYC loci during major transitions in B cell development when c-MYC transcription factor orchestrates many of their cell cycle regulation genes (bcl2, bcl6, TCF3, NFkB). As a consequence, IG/MYC translocations are frequently found and are used as associated biomarkers for the diagnostic of most fearsome B cell lymphomas with negative prognostic and poor treatment response. In this category one includes Acute B Lymphoblastic Leukemia(B-ALL), nonHodgkin B cell lymphomas(NHLB), cancers which will provide the phenotypic guiding markers to orient our study. We will establish correlative indices between each type of IG/MYC translocation topology found and the severity of phenotypic changes obtained in the selected  transformed B cell clones carrying such genomic lesions. These correlations should mirror the prototype of the guiding lymphoma cells found in human patients, and their surface markers will help in developing an efficient personalized therapy for their regression.