Abstract
Acute myeloid leukaemia (AML) is a disorder characterised by the accumulation of blast cells or progenitors of one of several non-lymphoid haematopoietic cell lineages and is classified into two types: primary and secondary. HOX genes are over-expressed in both AML and other cancers. This over-expression is associated with an intermediate/unfavourable cytogenetic subset of AML. Although HOX over-expression is a common feature of AML, conventional knockout methods have failed to fully evaluate their functions due to their functional redundancy. We have applied an alternative approach by using a synthetic peptide called HXR9 to antagonise the interaction between HOX proteins and their cofactor PBX, which interacts with HOX proteins in groups 1-10. AML cell lines derived from different AML types express different subsets of HOX genes at different levels due to the heterogeneity of AML. It is showed for the first time that targeting the HOX-PBX interaction using HXR9 led to cell death of the tested AML cell lines. This cell death did not appear to be through apoptosis, as there were no signs of the caspase activation and nuclear fragmentation. Likewise, there was also no activation of key necrotic markers such as cypD and PARP1. Instead, cell death involved, at least in part, the expression of c-FOS and p21 in p53-independentmanner. In addition, HXR9 caused cell death in MEK/ERK and p38 independent pathways, but the JNK pathway exerted a resistant effect in K562 cells. It was found that inhibiting the Ca2+ downstream mediators CaM, PKC and HO-1 significantly sensitised tested AML cell lines to HXR9. Taken together, these findings indicate a novel cell death pathway in AML cells. In vivo modelling also showed that HXR9 could delay tumour growth in a mouse model of AML.