Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells.
Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells.
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DOI：
10.1016/j.ebiom.2016.11.033
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Spaner DE
中科院分区：
文献类型：
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作者：
McCaw L;Shi Y;Wang G;Li YJ;Spaner DE
最近的研究表明，慢性淋巴细胞白血病 (CLL) 患者低密度脂蛋白 (LDL) 水平升高的发生率很高，降胆固醇他汀类药物可提高生存率。这些观察结果的机制及其适用的患者类型尚不清楚。使用 CLL 细胞起源的假滤泡的体外模型，发现 LDL 可以增加质膜胆固醇、酪氨酸磷酸化 STAT3 等信号分子和活化的 CLL 细胞数量。 LDL 的信号传导作用在正常淋巴细胞或糖酵解淋巴瘤细胞系中未见，但可通过核受体 PPARδ 转导而恢复，PPARδ 介导 CLL 细胞的代谢活动。放大效应需要溶酶体中 LDL 的分解，这与 HMGCR 表达的下调和 53.6 ± 10.4 个月的长淋巴细胞倍增时间 (LDT) 相关。在一个亚组患者中，循环 CLL 细胞的胆固醇含量与血液 LDL 水平直接相关。这些观察结果表明 LDL 可能增强 CLL 细胞对炎症信号的增殖反应。需要进行前瞻性临床试验来确认降低 CLL 中 LDL 浓度的治疗潜力，特别是对于处于“观察和等待”治疗阶段的惰性疾病患者。生长缓慢的 CLL 细胞使用溶酶体脂肪酶将低密度脂蛋白 (LDL) 分解为游离脂肪酸和胆固醇。 LdL 降解产物可提高增殖性 CLL 细胞的存活率。低密度脂蛋白可减少氧化应激并增加质膜胆固醇。 LDL 会放大增殖的 CLL 细胞中对细胞因子的信号反应，但不会放大对抗原的信号反应。快速生长的 CLL 细胞、急性白血病细胞和正常淋巴细胞不表现出对 LDL 的这种依赖性。
Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management. Slow-growing CLL cells use lysosomal lipase to break low density lipoproteins (LDLs) into free fatty acids and cholesterol. LdL degradation products increase survival of proliferating CLL cells. LDLs decrease oxidative stress and increase plasma membrane cholesterol. LDLs amplify signaling responses to cytokines but not antigens in proliferating CLL cells. Rapidly growing CLL cells, acute leukemia cells, and normal lymphocytes do not exhibit this dependence on LDLs.