XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis
Authors: Eline Boons, Tatiane C. Nogueira, Tim Dierckx, Soraya Maria Menezes, Maarten Jacquemyn, Sharon Tamir, Yosef Landesman, Lourdes Farré, Achiléa Bittencourt, Keisuke Kataoka, Seishi Ogawa, Robert Snoeck, Graciela Andrei, Johan Van Weyenbergh, Dirk Daelemans
Journal: Blood Cancer Journal (2021)

Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL).Although the majority of HTLV-1-infected individuals remain asymptomatic, in endemic regions such as Southern Japan, the Caribbean, some parts of Oceania, Romania, Central and South America, Northern Iran, and Central Africa, up to 4% of people living with HTLV-1 develop ATL.Although combination therapy with IFN-α and AZT as a first-line treatment prolongs survival of patients with ATL significantly, prognosis for patients with aggressive forms of ATL is poor due to intrinsic chemoresistance and relapse 1 .The viral proteins Tax and HBZ play a major role in HTLV-1-induced carcinogenesis 2 .Tax drives the ATL epigenetic signature through the NF-κB pathway and inactivates the tumor-suppressor protein p53 [3][4][5] .Inhibition of exportin-1 (CRM1/XPO1), the key nuclear export factor for proteins containing the typical leucine-rich nuclear export signal (NES), has been shown to inhibit NF-κB activity and induce p53-signaling pathways 6 , whereas XPO1 inhibitors display efficacy against different types of cancer [7][8][9] .Recently, the first-in-class XPO1 inhibitor selinexor (XPOVIO ® ) has been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and for relapsed diffuse large B-cell lymphoma.Selinexor is a highly selective and covalent inhibitor of XPO1 preventing export of cargo proteins to the cytoplasm, resulting in nuclear accumulation of cargo proteins [10][11][12] .Here, we investigate the therapeutic potential of selinexor in ATL by combining a two-stage targeted and systems analysis of ex vivo ATL transcriptomes with functional validation HTLV-1-transformed CD4+ cells.Since ATL leukemic cells are characterized as CD4 + CD25 + CADM1 + , we first investigated the possible relationship of XPO1 to these three signature genes, as well to p53 and NFκB signaling, which are the major regulators of apoptosis and survival in ATL [13][14][15] .As shown in Fig. 1A, ATL patients display an XPO1 hi phenotype as compared to healthy controls, which was significantly and positively correlated to ATL leukemic markers CD4, CD25/IL2RA and CADM1/TSCL1 in two independent patient cohorts from different HTLV-1 endemic areas (Brazilian cohort [13][14][15] , n = 9; Fig. 1C and Supplementary Fig. 1 for Japanese cohort [13][14][15] , n = 44).In contrast, a strong negative correlation between XPO1 and IL2RA was observed in PBMCs from healthy controls in the Brazilian cohort (Fig. 1A), which we validated in purified CD4+ cells from a large independent cohort of healthy controls (Supplementary Fig. 1, r = -0.23,p < 0.0001, n = 294).This suggests a pathobiological role for XPO1 in ATL leukemogenesis.Likewise, increased XPO1 transcript levels were found to be associated with clinical progression to aggressive ATL (Fig. 1B).Noteworthy, XPO1 expression neither differed between Hbz-high expressing (>10 transcripts per million, TPM) or Hbzlow expressing (<10 TPM) ATL patients, nor was there