Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer and leading cause of death in children. Glucocorticoids are critical components of multi-agent chemotherapy for ALL treatment and clinical response to glucocorticoids directly impacts patients’ survival. Significantly, the survival rate for children with glucocorticoid-resistant ALL is only 30-50% and so a strong unmet need remains to restore glucocorticoid sensitivity by developing more effective therapies for these hard-to-treat ALL cases.
We have demonstrated that the accessibility and epigenetic state of defined chromosome regions are linked to the initiation of apoptotic response following glucocorticoid treatment of chemo-sensitive ALL. Bioinformatic analysis of these regions showed enrichment for the binding motif of PU.1, a master transcriptional regulator in haematopoietic cells, with binding subsequently confirmed by ChIP-seq. We therefore sought to determine the role of PU.1 in mediating glucocorticoid response in ALL using an in vivo CRISPR gene editing system in patient-derived xenografts (PDX). Immune-deficient mice harbouring ALL PDX with PU.1 knock-out (KO), no KO (wild type, WT), or BIM KO (positive control) were treated with the standard preclinical course of Dexamethasone (glucocorticoid) and monitored for leukaemia relapse. Upon tracking the leukaemia burden post-treatment, loss of BIM expression, protein responsible for the apoptotic response following glucocorticoid treatment, showed increased drug resistance with significantly shorter event-free survival (EFSD) of 21 days (EFSD=EFSDexamethasone-EFSVehicle) compared to 29 days for the WT group. Significantly, ALL with PU.1 KO showed increased glucocorticoid sensitivity with mice having a longer EFSD of 39.3 days. Importantly, PU.1 KO alone did not affect leukaemia progression rate, indicating that PU.1 loss is not lethal to ALL survival. Our finding opens a new therapeutic pathway for including PU.1 inhibitors to the standard glucocorticoid chemotherapy regimen and editing of PU.1-bound gene regulatory elements to improve treatment response and patient survival.