Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-kB hyperactivation–induced senescence

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/ lymphoma (ATL). The HTLV-1 viral trans-activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21Cip1/Waf1 (p21)- and p27Kip1-mediated cellular senescence through constitutive activation (hyperactivation) of NF-kB. Although constitutive NF-kB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-kB activation without undergoing senescence. Here, we demonstrate that, in contrast to HTLV-12 T-cell lines, ATL cell lines no longer undergo Tax-induced senescence. Although Tax1 and Tax2 ATL cell lines showed signatures of constitutive NF-kB activation, their ability to progress through the cell cycle was unaffected. In some cases, ATL cell lines continued to proliferate despite significant upregulation of p21; additionally, many cell lines displayed altered expression of G1 and G1/S cyclins, particularly overexpression of cyclin D2. We propose that, during the course of ATL development, leukemia cells acquire genetic/epigenetic changes that can mitigate the senescence response triggered by NF-kB hyperactivation. Restoring the NF-kB–induced senescence response would likely help to control the development and progression of ATL and similar lymphoid malignancies.