The Pentose Phosphate Pathway Regulates Myelo-Lymphoid Lineage Specification
- 1Institut Curie
Abstract
Following infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we combined in situ RNA barcoding and metabolomics approaches to perform metabolic state-fate mapping in vivo. This approach revealed a subset of myeloid-biased HSPCs that express a distinct set of metabolic enzymes and transporters as well as the surface marker CD62L. Metabolically, CD62Lhigh HSPCs have differential activity of the pentose phosphate pathway (PPP), OXPHOS and translation, as well as differential levels of S-adenosylmethionine (SAM) cycle metabolites associated with epigenetic modifications. Inhibition of the PPP skews HSPC lineage fate decisions by disrupting myeloid associated enhancers, while simultaneously increasing enhancer activity for the master B-lymphoid regulator Ikaros. In vivo, overexpression of glucose-6-phosphate dehydrogenase, a rate limiting enzyme of the PPP, skewed HSPC output from B-lymphocytes. In summary, our data shows that HSPCs undergo significant metabolic changes to facilitate the bioenergetic and epigenetic demands of myeloid versus lymphoid lineage specification. We highlight a key role for the pentose phosphate pathway which modulates myeloid rather than lymphoid commitment by shaping the HSPC enhancer landscape, providing proof of principle that HSPC metabolism can be targeted to modulate immune system dynamics.
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BibTeX
@misc{cosgrove2026pentose,
title = {{The Pentose Phosphate Pathway Regulates Myelo-Lymphoid Lineage Specification}},
author = {J. cosgrove and A. Donada and A. M. Lyne and N. Krabacz and I. Rodriguez-Ramiro and A. Midoun and V. Cabeli and C. Conrad and G. Jouault and A. Durand and S. Teinreira and E. Tubeuf and H. Demollin and E. Russo and F. Cayrac and Y. Belloucif and S. Maleki and S. Reed and F. Monaco and L. Ruffinatto and B. de Laval and A. Ager and c. lobry and P. Bousso and P. J. Fernandez and C. Vallot and H. Isambert and N. Cabezas-Wallscheid and R. J. ARGUELLO and L. Perie},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.747966},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.747966v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The Pentose Phosphate Pathway Regulates Myelo-Lymphoid Lineage Specification
AU - J. cosgrove
AU - A. Donada
AU - A. M. Lyne
AU - N. Krabacz
AU - I. Rodriguez-Ramiro
AU - A. Midoun
AU - V. Cabeli
AU - C. Conrad
AU - G. Jouault
AU - A. Durand
AU - S. Teinreira
AU - E. Tubeuf
AU - H. Demollin
AU - E. Russo
AU - F. Cayrac
AU - Y. Belloucif
AU - S. Maleki
AU - S. Reed
AU - F. Monaco
AU - L. Ruffinatto
AU - B. de Laval
AU - A. Ager
AU - c. lobry
AU - P. Bousso
AU - P. J. Fernandez
AU - C. Vallot
AU - H. Isambert
AU - N. Cabezas-Wallscheid
AU - R. J. ARGUELLO
AU - L. Perie
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.747966
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.747966v1
AB - Following infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we combined in situ RNA barcoding and metabolomics approaches to perform metabolic state-fate mapping in vivo. This approach revealed a subset of myeloid-biased HSPCs that express a distinct set of metabolic enzymes and transporters as well as the surface marker CD62L. Metabolically, CD62Lhigh HSPCs have differential activity of the pentose phosphate pathway (PPP), OXPHOS and translation, as well as differential levels of S-adenosylmethionine (SAM) cycle metabolites associated with epigenetic modifications. Inhibition of the PPP skews HSPC lineage fate decisions by disrupting myeloid associated enhancers, while simultaneously increasing enhancer activity for the master B-lymphoid regulator Ikaros. In vivo, overexpression of glucose-6-phosphate dehydrogenase, a rate limiting enzyme of the PPP, skewed HSPC output from B-lymphocytes. In summary, our data shows that HSPCs undergo significant metabolic changes to facilitate the bioenergetic and epigenetic demands of myeloid versus lymphoid lineage specification. We highlight a key role for the pentose phosphate pathway which modulates myeloid rather than lymphoid commitment by shaping the HSPC enhancer landscape, providing proof of principle that HSPC metabolism can be targeted to modulate immune system dynamics.
ER -