@article{7fafcdce38f84165a6c2ad9a2fa1a402,
title = "Ascorbate regulates haematopoietic stem cell function and leukaemogenesis",
abstract = "Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo. Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which decreased with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, in part by reducing the function of Tet2, a dioxygenase tumour suppressor. Ascorbate depletion cooperated with Flt3 internal tandem duplication (Flt3ITD) leukaemic mutations to accelerate leukaemogenesis, through cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate therefore accumulates within HSCs to promote Tet activity in vivo, limiting HSC frequency and suppressing leukaemogenesis.",
author = "Michalis Agathocleous and Meacham, {Corbin E.} and Burgess, {Rebecca J.} and Elena Piskounova and Zhiyu Zhao and Crane, {Genevieve M.} and Cowin, {Brianna L.} and Emily Bruner and Murphy, {Malea M.} and Weina Chen and Spangrude, {Gerald J.} and Zeping Hu and DeBerardinis, {Ralph J.} and Morrison, {Sean J.}",
note = "Funding Information: Acknowledgements S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. M.A. was a Royal Commission for the Exhibition of 1851 Research Fellow. We thank F. Harrison for sharing the Slc23a2−/− mice, N. Loof and the Moody Foundation Flow Cytometry Facility for flow cytometry, K. Correll, A. Leach and A. Gross for mouse colony management and BioHPC at UT Southwestern for providing high-performance computing. This work was supported by the Cancer Prevention and Research Institute of Texas and the National Institutes of Health (R37 AG024945 and R01 DK100848). Publisher Copyright: {\textcopyright} 2017, Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2017",
month = sep,
day = "28",
doi = "10.1038/nature23876",
language = "English (US)",
volume = "549",
pages = "476--481",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7673",
}