Genomic alteration characterizing resistant CLL. The example of 2p+
Among the highly heterogeneous landscape of genomic abnormalities characterizing CLL, our team has focused in 2p+, a recurrent chromosomal abnormality associated with progressive disease. We have initially demonstrated that 2p+ was associated with XPO1, TTC27, BCL11A, REL, AHSA2, and USP34 overexpression, and that XPO1 plays a pivotal role in drug resistance (Cosson et al., Leukemia 2017). Our future work will unravel the specific role of these genes in CLL drug resistance in order to determine whether they cooperate with XPO1 in the apoptotic avoidance characterizing 2p+. Using a CRISPR-cas9 method, we will deactivate the different genes in a 2p+ drug resistant B-cell line (JVM-3). We also plan to overexpress the 2p+ genes in two 2p- CLL cell lines, OSU-CLL and HG3, using a classical dead-Cas9-VP64 transcriptional activation strategy. The consequences on drug resistance and cell proliferation will be assessed by classical flow cytometry approaches. Overall, by expanding the understanding of the key genes associated to a recurrent chromosomal abnormality in CLL, our work will have an important impact, resulting in gene biomarkers and strategies for precision medicine. This work will be carried out with several collaborations, in particular Dr. O Bernard’s team at IGR (Villejuif).