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, Sean J. Morrison

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)476-481
Number of pages6
JournalNature
Volume549
Issue number7673
DOIs
StatePublished - Sep 28 2017

Fingerprint

Hematopoietic Stem Cells
Stem Cells
Myelopoiesis
Dioxygenases
Metabolomics
Mutation
Population
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. / Agathocleous, Michalis; Meacham, Corbin E.; Burgess, Rebecca J.; Piskounova, Elena; Zhao, Zhiyu; Crane, Genevieve M.; Cowin, Brianna L.; Bruner, Emily; Murphy, Malea M.; Chen, Weina; Spangrude, Gerald J.; Hu, Zeping; DeBerardinis, Ralph J.; Morrison, Sean J.

In: Nature, Vol. 549, No. 7673, 28.09.2017, p. 476-481.

Research output: Contribution to journalArticle

Agathocleous, M, Meacham, CE, Burgess, RJ, Piskounova, E, Zhao, Z, Crane, GM, Cowin, BL, Bruner, E, Murphy, MM, Chen, W, Spangrude, GJ, Hu, Z, DeBerardinis, RJ & Morrison, SJ 2017, 'Ascorbate regulates haematopoietic stem cell function and leukaemogenesis', Nature, vol. 549, no. 7673, pp. 476-481. https://doi.org/10.1038/nature23876
Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017 Sep 28;549(7673):476-481. https://doi.org/10.1038/nature23876
Agathocleous, Michalis ; Meacham, Corbin E. ; Burgess, Rebecca J. ; Piskounova, Elena ; Zhao, Zhiyu ; Crane, Genevieve M. ; Cowin, Brianna L. ; Bruner, Emily ; Murphy, Malea M. ; Chen, Weina ; Spangrude, Gerald J. ; Hu, Zeping ; DeBerardinis, Ralph J. ; Morrison, Sean J. / Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. In: Nature. 2017 ; Vol. 549, No. 7673. pp. 476-481.
@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.}",
year = "2017",
month = "9",
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",

}

TY - JOUR

T1 - Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

AU - Agathocleous, Michalis

AU - Meacham, Corbin E.

AU - Burgess, Rebecca J.

AU - Piskounova, Elena

AU - Zhao, Zhiyu

AU - Crane, Genevieve M.

AU - Cowin, Brianna L.

AU - Bruner, Emily

AU - Murphy, Malea M.

AU - Chen, Weina

AU - Spangrude, Gerald J.

AU - Hu, Zeping

AU - DeBerardinis, Ralph J.

AU - Morrison, Sean J.

PY - 2017/9/28

Y1 - 2017/9/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85032919742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032919742&partnerID=8YFLogxK

U2 - 10.1038/nature23876

DO - 10.1038/nature23876

M3 - Article

C2 - 28825709

AN - SCOPUS:85032919742

VL - 549

SP - 476

EP - 481

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7673

ER -