Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche. (17th June 2019)

• Record Type: Journal Article
• Authors: Abdelhamed, Sherif; Butler, John T; Doron, Ben; Halse, Amber; Nemecek, Eneida; Wilmarth, Phillip A; Marks, Daniel L; Chang, Bill H; Horton, Terzah; Kurre, Peter
• Is Part Of: EMBO reports. Volume 20:Number 7(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-06-17
• Subjects: AML -- DNA damage -- extracellular vesicles -- hematopoiesis; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201847546
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Acute myeloid leukemia (AML) functionally remodels the bone marrow niche. AML cells constitutively release extracellular vesicles (EVs) enriched in miR‐1246, that traffic to long‐term hematopoietic stem cells (LT‐HSC) and induce quiescence and DNA damage. Following EV uptake into LT‐HSC, miR‐1246 downregulates the Regulatory‐associated protein of mTOR (Raptor) leading to the hypo‐phosphorylation and deregulation of S6 ribosomal protein (S6RP). Deregulation of the S6RP mediates protein synthesis suppression associated with P53‐dependent quiescence. While quiescence and protein synthesis suppression are reversible upon transfer to naïve recipients, cells accrue double‐strand DNA‐breaks that persist, and generate a long‐lasting DNA‐damage response (DDR) while conferring gains in proliferative capacity. Abstract : Acute myeloid leukemia functionally remodels the bone marrow niche. AML cells constitutively release extracellular vesicles enriched in miR‐1246, that traffic to long‐term hematopoietic stem cells and induce quiescence and DNA damage.