Characterization Of Plasma-Derived Exosomes In Cll Reveals A Distinct Microrna Signature And The Bcr Regulation In Exosome Secretion

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAChronic lymphocytic leukemia (CLL) is the most diagnosed adult leukemia and has a very heterogeneous clinical course attributed to its defective apoptosis and sustained nurture of the microenvironment. In vivo, CLL resides in close contact with T lymphocytes, stromal cells, monocyte-derived nurse-like cells, follicular dendritic cells, and macrophages, collectively referred to as the “microenvironment.” Interactions between these components result in CLL cell trafficking, survival, proliferation, and anti-apoptosis, which may be partly dependent on direct cell-to-cell contact or mediated through the soluble factors, including the secreted extracellular vesicles (EVs) as an alternative means for intercellular communications. These EVs have distinct biochemical properties and contain cellular components, such as proteins, lipids, mRNAs and microRNAs (miRs). Exosomes are EVs with 40 - 100nm in diameter and considered to initiate from the late endosomal membrane, giving rise to intracellular multivesicular bodies that later fuse with the plasma membrane and release the exosomes to the exterior. The secretion of exosomes has been reported to be regulated by intracellular calcium levels, activation of the cell surface receptor or stress responses. Emerging evidence suggests that cancer releases large amount of exosomes and exosome functions in recipient cells are associated with tumor immune response, metastasis, tumorigenesis, angiogenesis, drug resistance, and changes in signaling transduction. With increasing evidence implicating the importance of these EVs, it prompts us to elucidate the exosome biochemical property and to investigate the relevance of exosome in CLL.Our data demonstrate that CLL releases high levels of exosomes in plasma than healthy donor and its concentration is not associated with the absolute lymphocyte count. These CLL plasma-derived exosomes express abundant CD63, CD9 and CD37 but not CD41, CD3 or CD56. Activation of BCR by α-IgM stimulation induces CLL to release more exosomes while inhibition of BCR via ibrutinib, a BTK inhibitor, abrogates α-IgM induced exosome secretion. Moreover, analyzing plasma samples collected on an ibrutinib phase 2 clinical trial (OSU-11133, [NCT01589302][1]), the exosome concentration decreases in post ibrutinib treatment. In addition, profiling the exosome miR isolated from 69 CLL and 15 healthy donors reveals a distinct miR signature, including up-regulation of miR-29 family, miR-155, miR-150 and down-regulation of miR-223 that have been shown to be associated with the CLL disease. In all, we have successfully characterized the composition of CLL exosome with the optimal methods and demonstrated the control of BCR signaling in the CLL exosome release. Furthermore, the identified CLL exosome miR profile can be explored further to uncover the exosome function and its relevance to the CLL disease.Citation Format: Yuh-Ying Yeh, Hatice Gulcin Ozer, Amy M. Lehman, Lianbo Yu, Amy J. Johnson, John C. Byrd. Characterization of plasma-derived exosomes in CLL reveals a distinct microRNA signature and the BCR regulation in exosome secretion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2015-3985 [1]: /lookup/external-ref?link_type=CLINTRIALGOVu0026access_num=NCT01589302u0026atom=%2Fcanres%2F75%2F15_Supplement%2F3985.atom