## 1 Introduction  
Leukaemia is a myeloproliferative disorder characterised by uncontrolled proliferation of immature blasts in the bone marrow, eventually penetrating into the bloodstream, preventing normal haematopoiesis [1, 2]. Such blasts suffer an obstruction during early development, referred to as a maturation arrest, and fail to reach functional maturity [3, 4]. In acute promylocytic leukaemia (APL), this arrest may be reversed by using all _trans_ retinoic acid (ATRA), an approach called differentiation therapy, that has completely altered this leukaemia's prognosis [5, 6]. It generally shows less toxic side effects than chemotherapy [7]. Hence, reproducing the success of differentiation therapy on different leukaemia types is a much sought-after goal.  
The HL-60 cell line consists of immature cells arrested at the myeloblast-promylocyte stage and is well- characterised in terms of the induction of terminal differentiation down either the monocytic or granulocyte pathway. Dimethyl sulfoxide (DMSO) and ATRA drive HL-60 to granulocyte differentiation, whilst 1,25-dihydroxy vitamin D3, sodium butyrate and phorbol esters drive them towards monocytes/macrophages [8]. Such maturation is accompanied by a reduction in cell size, the condensation of nuclear material, and changes in cell surface antigens such as CD11b and CD14 surface markers [8, 9, 10]. Gene expression analysis in differentiating HL-60 treated cells show an increase in genes associated with the oxidative burst [11; 12], cytokine upregulation [13], adhesion, and trans-endothelial migration such ICAM adhesion molecules [12; 14]. Following differentiation, an increase in the expression of apoptotic-related genes may follow as these cells naturally die, which is the end point of successful differentiation therapy [14; 15].  
Polyphenols are a group of highly diverse molecules found extra virgin olive oils (EVOOs) and other plant sources and are associated with chemo-preventive functions and differentiation-inducing properties [16]. They are secondary metabolites that appear to offer protection against solar irradiation as well as anti-microbial and anti-pathogenic activity. They are classified into phenolic acids (hydroxycinnamic and hydroxybenzoic acids), phenolic alcohols, lignans, stilbenes, secoriridoids, coumarins, xanthones, and flavonoids. The major components of the phenolic fraction in EVOOs are tyros, hydroxytyrosol, and their derivatives [17]. The former, tyrosol, is known to increase in concentration during olive oil storage [18]. The phenolic profiles of Maltese EVOOs have been characterized by [PERSON] et al., 2019 and [PERSON] et al., 2021 [19; 20].  
Differentiation-induction in leukaemia has been attributed to oleuropein, apigenin-7-glucoside, hydroxytyrosol, the dialdehyde compound of elenoic acid linked to hydroxytyrosol, as well as pinoresinol, amongst EVOO-derived polyphenols [21; 22; 23]. Moreover, hydroxytyrosol was noted to bring about HL-60 cell proliferation arrest at the G\({}_{0}\)/G\({}_{1}\) phase and upregulate the cyclin-dependent protein kinase inhibitors p21 WAF1/CIP1 and p27 KIP1 [24]. transcriptomic studies in AML models following phenolic administration do not appear to be published.  
This study investigated whether tyrosol could induce HL-60 differentiation using biochemical and morphological assays. The effects on the cell cycle, as well as the transcriptomic changes following exposure to tyrosol treatment, were then explored. Changes to the NFkB pathway and the Interferon Regulatory Factors network are identified.