Yeh Yuh-Ying, Ozer Hatice Gulcin, Lehman Amy M, Maddocks Kami, Yu Lianbo, Johnson Amy J, Byrd John C
Division of Hematology, Department of Internal Medicine.
Department of Biomedical Informatics.
Blood. 2015 May 21;125(21):3297-305. doi: 10.1182/blood-2014-12-618470. Epub 2015 Apr 1.
Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.
多项研究表明，慢性淋巴细胞白血病（CLL）细胞的存活严重依赖其微环境。CLL细胞与微环境之间的通讯通过直接细胞接触、可溶性因子和细胞外囊泡介导。外泌体是包裹着脂质、蛋白质和小RNA的小颗粒，能够将生物物质传递给周围细胞。我们在此的数据表明，CLL细胞在血浆中释放大量外泌体，这些外泌体表现出丰富的CD37、CD9和CD63表达。我们的工作还明确了B细胞受体（BCR）信号传导在CLL外泌体释放中的调节作用：α-免疫球蛋白（Ig）M激活BCR可诱导外泌体分泌，而通过依鲁替尼使BCR失活则会阻碍α-IgM刺激的外泌体释放。此外，对参加依鲁替尼临床试验的CLL患者采集的系列血浆样本分析显示，依鲁替尼治疗后外泌体血浆浓度显著降低。此外，对血浆来源外泌体的微小RNA（miR）分析确定了一种独特的外泌体微小RNA特征，包括与CLL疾病相关的miR-29家族、miR-150、miR-155和miR-223。有趣的是，外泌体miR-150和miR-155的表达随BCR激活而增加。总之，本研究成功地对CLL外泌体进行了表征，证明了BCR信号传导对CLL外泌体释放的控制，并揭示了与疾病相关的外泌体微小RNA谱。
