Multi-level systems analysis identifies XPO1 as a druggable target linked to NFκB activation, proliferation, tumor clonality and long-term survival in Adult T-cell Leukemia

Adult T-cell leukemia (ATL), an aggressive malignancy triggered by human T-cell leukemia virus-1 (HTLV-1), has a dismal prognosis and limited therapeutic options. Here, we investigate the nuclear export protein XPO1 as a critical driver of ATL proliferation and a promising therapeutic target. We used a multi-level approach, combining systems biology analysis of three independent ATL patient cohorts with in vitro functional validation. Our systems analysis revealed that XPO1 expression is significantly elevated and differentially spliced in acute ATL, and is central to a pro-proliferative gene module, positively correlated with both the ATL transcriptional signature and tumor clonality. This ex vivo link was confirmed in vivo in four unique long-term surviving patients, for which successful therapy with IFN-α+AZT led to a concurrent decrease in XPO1 and key proliferation marker PCNA . Furthermore, we demonstrated that pharmacological inhibition of XPO1 with the clinical-stage compound Selinexor (KPT-330) and a related SINE compound, KPT-185, decreased proliferation and induced apoptosis in HTLV-1-transformed cells. Mechanistically, XPO1 inhibition exerted its anti-tumor effect by dismantling the pro-survival NF-κB pathway. Our combined findings establish XPO1 as a relevant therapeutic target in ATL and suggest its possible use as a biomarker for therapeutic response.