The targeting effect of Hm2E8b–NCTD–liposomes on B-lineage leukaemia stem cells is associated with the HLF–SLUG axis

Abstract

To identify an agent with specific activity against B-lineage leukaemia stem cells (B-LSCs), we generated norcantharidin (NCTD)-encapsulated liposomes modified with a novel humanised anti-human CD19 monoclonal antibody, Hm2E8b (Hm2E8b–NCTD–liposomes). These liposomes were specially designed to recognise and kill B-LSCs in vitro, and to decrease non-specific cytotoxicity to untargeted cells. Hm2E8b–NCTD–liposomes selectively ablated B-LSCs through targeting hepatic leukaemia factor (HLF), which is implicated in haematopoietic stem cell regulation and is overexpressed in LSCs. Hm2E8b–NCTD–liposomes decreased HLF protein levels and induced apoptosis in the HAL-01 cell line harbouring the oncoprotein E2A–HLF. This resulted in modulation of the expression of several molecules that govern survival pathways, including HLF, SLUG, NFIL3 and C-Myc, thereby causing the induction of p53 and the mitochondrial caspase cascade. Therefore, the potent in vitro effect of Hm2E8b–NCTD–liposomes on B-LSC activity and survival pathways have the potential to be exploited clinically with appropriate drug combinations.

Keywords:

• Hm2E8b
• immunoliposome
• leukaemia stem cells
• norcantharidin
• targeting

Acknowledgements

We would like to thank Professor Yi Jin at Zhejiang University School of Pharmacy for his critical comments and kind suggestions.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This project was partially supported by grants from National Natural Science Foundation of China [NO: 81200386, NO: 81170502], Natural Science Foundation of Zhejiang Province [NO: LQ12H08003, NO: Z205166], Specialized Research Fundation for Doctoral Program of Higher Education [NO: 20110101120140] and Leukemia Research Innovative Team of Zhejiang Province [No: 2011R50015].