Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD.
Blood Adv. 2019 Feb 26;3(4):564-569. doi: 10.1182/bloodadvances.2018029322.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL). The HTLV-1 viral -activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21 (p21)- and p27-mediated cellular senescence through constitutive activation (hyperactivation) of NF-κB. Although constitutive NF-κB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-κB activation without undergoing senescence. Here, we demonstrate that, in contrast to HTLV-1 T-cell lines, ATL cell lines no longer undergo Tax-induced senescence. Although Tax and Tax ATL cell lines showed signatures of constitutive NF-κB 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-κB hyperactivation. Restoring the NF-κB-induced senescence response would likely help to control the development and progression of ATL and similar lymphoid malignancies.
人类 T 细胞白血病病毒 1 型（HTLV-1）是成人 T 细胞白血病/淋巴瘤（ATL）的病因。HTLV-1 病毒激活物/癌蛋白 Tax 是 ATL 的主要驱动因素，但它通过 NF-κB 的组成性激活（过度激活）诱导快速的 p21（p21）和 p27 介导的细胞衰老。尽管组成性 NF-κB 激活是 T/B 细胞白血病/淋巴瘤的共同特征，包括 ATL，但尚不清楚 ATL 细胞如何在不经历衰老的情况下维持慢性 NF-κB 激活。在这里，我们证明与 HTLV-1 T 细胞系相反，ATL 细胞系不再经历 Tax 诱导的衰老。尽管 Tax 和 Tax ATL 细胞系表现出组成性 NF-κB 激活的特征，但它们通过细胞周期的能力不受影响。在某些情况下，尽管 p21 显著上调，ATL 细胞系仍继续增殖；此外，许多细胞系表现出 G1 和 G1/S 周期蛋白的表达改变，特别是 cyclin D2 的过度表达。我们提出，在 ATL 发展过程中，白血病细胞获得遗传/表观遗传变化，可以减轻 NF-κB 过度激活引发的衰老反应。恢复 NF-κB 诱导的衰老反应可能有助于控制 ATL 和类似淋巴恶性肿瘤的发展和进展。
