Deciphering STAT3 dependency in paediatric acute lymphoblastic leukemia

Although there have been tremendous advances in the successful treatment of paediatric ALL, this disease contributes to half of all leukaemia deaths in children. Development of new, broad range therapies is urgently needed. In this project we focused our attention on STAT3 in B-ALL, investigating the STAT3 regulated pathways. Global gene expression changes in B-ALL REH cells following pharmacological inhibition and shRNA-mediated silencing of STAT3 highlighted induction of TP53 target genes, without significant changes in TP53 mRNA. Indeed, STAT3 inhibition led to increased TP53 protein levels and to increased expression of TP53-target genes. Loss of TP53 expression in CRISPR/Cas9-generated TP53-/- REH cells resulted significant attenuation of REH sensitivity to STAT3 inhibition. We have also discovered that susceptibility to STAT3 inhibition is much broader in patient-derived xenograft (PDX) B-ALL subtypes than previously noted in cell lines, and that it correlates with TP53 status. Our results indicate a functional link between STAT3 and TP53 in B-ALL. STAT3 inhibition coupled with TP53 induction could represent a novel therapeutic strategy in B-ALL.

Publication History

Article published online:
13 May 2020