Dysregulation of splicing factors in B-cell acute lymphoblastic leukemia

A. Thomas-Tikhonenko
2019 Biopolymers and Cell  
Recently we discovered a novel mechanism explaining how B-cell lymphomas might be induced during HIV infections� HIV-positive subjects have an increased risk to develop specific lymphoma subtypes including Burkitt lymphoma (BL)� We recently found that viral transactivator of transcription (Tat) protein, which is released by infected cells into the blood stream, could remodel the B-cell nucleus bringing together the potential translocation partners, the MYC loci at the chromosome 8 and the IGH
more » ... ome 8 and the IGH loci at the chromosome 14, thus increasing the probability of the t(8;14) translocation characteristic of BL� Tat induces the mobility of the MYC locus in the nucleus via induction of DSB in the vicinity of the MYC gene and its further repair by NHEJ� In order to study the mechanism of the DSB/NHEJinduced locus relocalization, we have created and characterized the lymphoblastoid RPMI8866 cell line inducibly expressing CRISPR/Cas9 and gRNA targeting the upstream region of the MYC IGH genes� Upon induction, This leads to relocalization of the MYC locus towards the center of the nucleus and the IGH CRISPR/Cas9 generates DBDs in the target loci as well as t(8;14) transloca-tions� Factors that increase the proximity between the MYC and IGH loci also increase the t(8;14) frequency and inversely, drugs that inhibit proximity also inhibit the translocation frequency. Therefore, we provide here the first experimental proof that spatial proximity indeed increases the probability of chromosomal translocations�
doi:10.7124/bc.0009c7 fatcat:faofecfg45dyxoljpkkukhqyry