Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology.
Department of Biology.
Blood. 2014 Sep 25;124(13):2072-80. doi: 10.1182/blood-2014-03-560060. Epub 2014 Jul 17.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.
成人 T 细胞白血病/淋巴瘤（ATL）是由人类 T 细胞白血病病毒 1 型（HTLV-1）引起的侵袭性肿瘤。HTLV-1 癌蛋白 Tax 在 ATL 发病机制中起重要作用。由于化疗耐药，ATL 预后不良，这强调了需要替代疗法。在这里，我们研究了合成视黄醇 ST1926 在 ATL 和外周 T 细胞淋巴瘤中的临床前疗效。临床可达到的 ST1926 浓度可显著抑制恶性 T 细胞系和原发性 ATL 细胞的细胞增殖，而对静止或激活的正常淋巴细胞的影响最小。ST1926 在恶性 T 细胞中诱导细胞凋亡、DNA 损伤和 p53 蛋白上调，而在 HTLV-1 阳性细胞中导致 Tax 蛋白的早期下调。在鼠 ATL 中，口服 ST1926 治疗可延长生存期并减少白血病细胞浸润、白细胞计数和脾脏质量。在 ST1926 治疗动物的脾脏中，p53 和 p21 蛋白上调，多聚（ADP-核糖）聚合酶被切割，Tax 转录物减少。这些结果突出了 ST1926 作为 ATL 靶向治疗的有前途的用途。
