Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

Michalis Agathocleous, Corbin E. Meacham, Rebecca J. Burgess, Elena Piskounova, Zhiyu Zhao, Genevieve M. Crane, Brianna L. Cowin, Emily Bruner, Malea M. Murphy, Weina Chen, Gerald J. Spangrude, Zeping Hu, Ralph J. DeBerardinis and Sean J. Morrison ()
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Michalis Agathocleous: University of Texas Southwestern Medical Center
Corbin E. Meacham: University of Texas Southwestern Medical Center
Rebecca J. Burgess: University of Texas Southwestern Medical Center
Elena Piskounova: University of Texas Southwestern Medical Center
Zhiyu Zhao: University of Texas Southwestern Medical Center
Genevieve M. Crane: University of Texas Southwestern Medical Center
Brianna L. Cowin: University of Texas Southwestern Medical Center
Emily Bruner: University of Texas Southwestern Medical Center
Malea M. Murphy: University of Texas Southwestern Medical Center
Weina Chen: University of Texas Southwestern Medical Center
Gerald J. Spangrude: University of Utah
Zeping Hu: University of Texas Southwestern Medical Center
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Sean J. Morrison: University of Texas Southwestern Medical Center

Nature, 2017, vol. 549, issue 7673, 476-481

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature23876

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