PO.MCB02.02 · 分子与细胞生物学
前列腺素E2增加急性淋巴细胞白血病中脂滴积累和滴周线粒体数量
Prostaglandin E2 increases lipid droplet accumulation and peri-droplet mitochondria population in acute lymphoblastic leukemia
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摘要 Abstract
中文摘要
急性淋巴细胞白血病(ALL)是最常见的儿童癌症,约占所有儿科恶性肿瘤的70%。虽然部分患者在接受强化化疗方案后获得缓解,但已发现多种人口学和生物学因素会使治疗结局恶化。以体重指数(BMI)临床定义的肥胖与生存率降低、化疗毒性增加以及复发风险增加密切相关。我们实验室此前已证明,脂肪组织为ALL细胞提供游离不饱和脂肪酸和氨基酸,并保护细胞免受化疗影响。为鉴定脂肪组织改变ALL代谢的机制,我们此前在小鼠上进行了单细胞RNA测序实验,比较脂肪组织与骨髓中ALL细胞的基因表达谱。该实验揭示了脂肪组织前列腺素E2(PGE2)合成与ALL细胞脂滴成熟之间的潜在联系。为探索这一点,我们将人BV173和RS4-11 ALL细胞在transwell小室中与来自UCLA转化病理学核心平台的人内脏脂肪组织外植体共培养。与脂肪组织共培养增加了ALL细胞脂滴相关蛋白perilipin(PLIN)2和5的基因及蛋白表达(n=4-8)。随后我们用PGE2(200ng/mL)处理ALL细胞,观察到PLIN2和PLIN5的基因及蛋白表达增加(n=3-4)。共聚焦成像证实,PGE2在人ALL细胞系中诱导脂滴形成,并伴有滴周线粒体——一种已知促进脂滴合成的特化线粒体亚群。我们推测脂肪组织PGE2诱导ALL细胞脂滴积累和滴周线粒体形成,这些可能有助于保护ALL细胞免受细胞毒性作用。
与人脂肪外植体共培养的人ALL细胞中PLIN5和PLIN2的基因及蛋白表达 BV173 BV173 BV173 RS4;11 RS4;11 RS4;11 平均值 +/- SD P值 n 平均值 +/- SD P值 n PLIN5基因 3.6±2.0 <0.0001 6 3.6±2.8 0.03 4 PLIN2基因 1.2±0.3 无统计学意义 6 1.9±0.8 无统计学意义 4 PLIN5蛋白 1.3±0.2 0.01 7 1.5±0.5 0.02 8 PLIN2蛋白 2.3±0.6 0.002 6 2.0±0.8 0.02 8
查看英文原文 English abstract
Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, representing approximately 70% of all pediatric malignancies. While some patients attain remission following intensive chemotherapy regimens, multiple demographical and biological factors have been identified that worsen treatment outcomes. Obesity, clinically defined by body mass index (BMI), has been strongly associated with reduced survival rates, increased toxicity from chemotherapy, and increased risk of relapse. Our laboratory has previously demonstrated that adipose tissue supplies free unsaturated fatty acids and amino acids to ALL cells and protects the cells from chemotherapy. To identify the mechanisms by which adipose tissue alters the metabolism of ALL, we previously performed a single-cell RNA sequencing experiment on mice to compare the gene expression profiles of ALL cells between adipose tissue and bone marrow. This experiment uncovered a potential link between adipose tissue prostaglandin E2 (PGE2) synthesis and ALL cell lipid droplet maturation. To explore this, we cocultured human BV173 and RS4-11 ALL cells in transwell inserts above human visceral adipose tissue explants obtained from UCLA's Translational Pathology Core. Coculture with adipose tissue increased ALL cell lipid droplet-associated proteins perilipin (PLIN) 2 and 5 gene and protein expression (n=4-8). We next treated ALL cells with PGE2 (200ng/mL) and observed increased gene and protein expression in PLIN2 and PLIN5 (n=3-4). Confocal imaging confirmed that PGE2 induced lipid droplets in human ALL cell lines, along with peri-droplet mitochondria, a specialized subset of mitochondria known to promote lipid droplet synthesis. We hypothesize that adipose tissue PGE2 induces ALL cell lipid droplet accumulation and peri-droplet mitochondria formation and that these may contribute to protecting ALL cells from cytotoxicity.
PLIN5 and PLIN2 gene and protein expression in human ALL cells cocultured w human adipose explants BV173 BV173 BV173 RS4;11 RS4;11 RS4;11 mean +/- SD P-value n mean +/- SD P-value n PLIN5 gene 3.6±2.0 <0.0001 6 3.6±2.8 0.03 4 PLIN2 gene 1.2±0.3 n.s 6 1.9±0.8 n.s 4 PLIN5 protein 1.3±0.2 0.01 7 1.5±0.5 0.02 8 PLIN2 protein 2.3±0.6 0.002 6 2.0±0.8 0.02 8
利益披露 Disclosure
B. Shabane, None..
C. Beninca, None..
M. Cohen, None..
N. Scillitani, None..
U. Ihenacho, None..
O. Shirihai, None..
S. D. Mittelman, None.