Globally, over 80,000 people die from Acute Myeloid Leukaemia (AML) each year, with the average 5-year survival rate presently resting at ~30%. Although most of the underlying genetic mutations have been identified, the inherent genetic heterogeneity across patients remains a limiting factor for current targeted therapies. Our lab has recently discovered that high SNAI1 expression is a frequent event in AML, with more than half of AML patients presenting with upregulated SNAI1 expression1. SNAI1 is one of many transcriptional regulators responsible for the epithelial-to-mesenchymal transition (EMT) process, a well-known oncogenic driver of tumour metastasis and chemoresistance, particularly in solid cancers. Only recently has SNAI1 and the EMT process become affiliated with haematological development and malignancy, although the mechanisms by which SNAI1 drives pathogenesis have yet to be unravelled. We have shown SNAI1 overexpression in haematopoietic stem and progenitor cells (HSPCs) of mice induces a myeloproliferative phenotype with progression into AML. Moreover, we have found SNAI1 drives pathogenicity through a physical interaction with LSD1, a histone demethylase known to interact with a multitude of haematopoietic transcription factors to regulate HSPC function and myeloid differentiation1. Interestingly, additional unpublished data from our lab has revealed that SNAI1 expression in HSPCs in vitro drives the activation of NF-kB inflammatory signalling pathways. Critically, these findings agree with a correlation observed between upregulated SNAI1 expression and NFkB activation across AML patients. Our AML mouse model also supports our preliminary data with the upregulation of inflammatory mediators and development of myelofibrosis, an inflammatory-mediated event. Ongoing works have been put in place to further examine the extent of SNAI1’s responsibility in promoting the inflammatory and pathogenic signatures observed in our models.
Targeting SNAI1 chemically is so far, not possible. We have developed in vitro and in vivo models capable of transcriptionally modifying and tracking SNAI1 expression. We aim to utilise these models to reveal new SNAI1-associated pathogenic weaknesses which may be therapeutically targeted to improve the efficacy of the current treatment regimes.