HOPX as a tumour‐suppressive protein in T‐cell acute lymphoblastic leukaemia

The homeodomain protein homeobox (HOPX), a multifaceted regulator of cellular functions and developmental processes, is predominantly expressed in stem cells across diverse tissues; it has also emerged as a tumour suppressor in various solid cancers. However, its role in haematological malignancies still remains undefined. This study aimed to elucidate its significance in T-cell acute lymphoblastic leukaemia (T-ALL). We firstly uncovered a novel link between reduced HOPX expression, its promoter hypermethylation and increased tumour burden in patients with T-ALL, suggesting its tumour-suppressive role. Next, we induced T-ALL by transducing intracellular NOTCH1 (ICN1) into mice with either conditional knock-in at the Rosa26 locus or knockout of Hopx. We found that T-ALL development was markedly accelerated and impeded in backgrounds with low and high Hopx expression respectively. Further analysis revealed Hopx's roles in modulating the Wnt-β-catenin pathway, a pivotal regulator of the downstream Myc signalling involved in T-ALL transformation and progression.