Genome-wide CRISPR screen in patient derived cells reveals the mechanism of ALL chemoresistance

ALL (acute lymphoblastic leukaemia) treatment is associated with significant infection-related mortality that comes as a consequence of currently used genotoxic drugs. Despite of therapy improvement, occurrence of cancer relapse results in a relatively poor outcome and still remains one of the major therapeutic challenges. Here, we performed a study to investigate the mechanism of dexamethasone resistance in a model of TCF3-HLF (t(17;19)-positive) ALL. We have performed a genome-wide CRISPR screen in patient-derived xenografts (PDX) both in vitro and in vivo. For the in vitro approach we have used co-culture system of patient-derived material with different types of human stromal cells (mesenchymal and endothelial-like), which allowed us to recreate oncogenic microenvironment as well as to provide support for growth and proliferation of primary ALL samples in vitro. We have identified the glucocorticoid receptor NR3C1 as the gene which deletion possibly drives the mechanism of chemoresistance in this type of high risk ALL. Most importantly, we have shown that genome-wide screens are able to predict the relapse in primary ALL samples.