@article{f3706984b79a4e86a4c2bccec54f35da,
title = "Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche",
abstract = "Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding acute myeloid leukemia (AML) clones not only alter stroma composition, but also actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long-term hematopoietic stem cells (LT-HSC) to elimination from the leukemic niche. Here, we examine the fate and function of residual LT-HSC in the BM of murine xenografts with emphasis on the role of AML-derived extracellular vesicles (EV). AML-EV rapidly enter HSC, and their trafficking elicits protein synthesis suppression and LT-HSC quiescence. Mechanistically, AML-EV transfer a panel of miRNA, including miR-1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo-phosphorylation, which in turn impairs protein synthesis in LT-HSC. While HSC functionally recover from quiescence upon transplantation to an AML-naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double-strand breaks and evidence of a sustained DNA-damage response. In sum, AML-EV contribute to niche-dependent, reversible quiescence and elicit persisting DNA damage in LT-HSC.",
keywords = "AML, DNA damage, extracellular vesicles, hematopoiesis",
author = "Sherif Abdelhamed and Butler, {John T.} and Ben Doron and Amber Halse and Eneida Nemecek and Wilmarth, {Phillip A.} and Marks, {Daniel L.} and Chang, {Bill H.} and Terzah Horton and Peter Kurre",
note = "Funding Information: This study was supported by a Hyundai Hope on Wheels Scholar Grant, Max Blue Butterfly Campaign (P.K), and the OHSU Medical Research Foundation (S.A). The authors thank Dr. William H. Fleming, Dr. Devorah Goldman, and Dr. Mu-shui Dai (OHSU) for their critical feedback; members of the OHSU flow cytometry core, Pamela Canaday and Dorian LaTocha, for cell sorting assistance; and Dr. Claudia Lopez for the electron microscopy analysis at the Multi-scale Microscopy Core (MMC) at the OHSU Center for Spatial Systems Biomedicine (OCSSB). Mass spectrometric analysis was performed by the OHSU Proteomics Shared Resource with partial support from NIH grants P30EY010572, P30CA069533, and S10OD012246. We would also like to thank Dr. Noah Hornick, Dr. Santhosh C. Verghese, Dr. Makiko Mochizuki-Kashio, and Lotte Tholen for helpful discussions. Funding Information: This study was supported by a Hyundai Hope on Wheels Scholar Grant, Max Blue Butterfly Campaign (P.K), and the OHSU Medical Research Foundation (S.A). The authors thank Dr. William H. Fleming, Dr. Devorah Goldman, and Dr. Mu-shui Dai (OHSU) for their critical feedback; members of the OHSU flow cytometry core, Pamela Canaday and Dorian LaTocha, for cell sorting assistance; and Dr. Claudia Lopez for the electron microscopy analysis at the Multiscale Microscopy Core (MMC) at the OHSU Center for Spatial Systems Biomedicine (OCSSB). Mass spectrometric analysis was performed by the OHSU Proteomics Shared Resource with partial support from NIH grants P30EY010572, P30CA069533, and S10OD012246. We would also like to thank Dr. Noah Hornick, Dr. Santhosh C. Verghese, Dr. Makiko Mochizuki-Kashio, and Lotte Tholen for helpful discussions. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jul,
doi = "10.15252/embr.201847546",
language = "English (US)",
volume = "20",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "7",
}