---
title: "Physiological folate limits dNTP synthesis and makes leukemia cells rely on nucleotide salvage"
id: "biorxiv-4-physiological-folate-levels-constrain-nucleotide-synthesis-and-increase"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-4-physiological-folate-levels-constrain-nucleotide-synthesis-and-increase"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.13.750663v1?rss=1"
published_at: "2026-09-14T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Physiological folate limits dNTP synthesis and makes leukemia cells rely on nucleotide salvage
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-4-physiological-folate-levels-constrain-nucleotide-synthesis-and-increase
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.13.750663v1?rss=1)
- **Published At:** 2026-09-14T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Researchers used a mouse plasma-like medium (MPM) modeled on circulating metabolites from mice with B-cell acute lymphoblastic leukemia (**B-ALL**) to study how physiological nutrient levels affect nucleotide acquisition. - In MPM, leukemia cells primarily acquire nucleotides via **nucleotide salvage** pathways rather than de novo synthesis observed under standard culture conditions. - Certain nucleotide salvage pathways are required for proliferation of B-ALL cells under plasma-like conditions; disrupting these pathways impairs proliferation. - The increased dependence on salvage was not due to limited precursor metabolites for de novo nucleotide synthesis, according to the study. - Instead, the authors found that **physiological folate** levels are insufficient to support deoxynucleotide triphosphate (**dNTP**) synthesis needed for genome replication in these conditions. - Folate insufficiency led to DNA replication stress and reduced proliferation when nucleotide salvage pathways were disrupted. - Dietary folate restriction in vivo worsened the impaired leukemia progression phenotype of nucleotide salvage–deficient B-ALL cells, supporting the in vitro findings. - The study highlights that micronutrient availability, specifically folate abundance, can shape metabolic dependencies relevant to leukemia progression and the importance of salvage pathways under physiological nutrient conditions. - Funding sources and disclosures are reported; one author (M.G.V.H.) lists multiple scientific advisory roles. Other authors declared no competing interests.
## Clinical Analysis & Structured Key Points
Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage | bioRxiv Skip to main content New Results Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage View ORCID Profile Ryan Elbashir , View ORCID Profile Keene L. Abbott , Diya L. Ramesh , Ahmed Ali , Anna Shevzov-Zebrun , Anna M. Barbeau , Michelle Wu , Abigail P. Ward , Yetis Gultekin , Brian T. Do , View ORCID Profile Sharanya L Sivanand , Azucena Ramos , Tenzin Kunchok , Millenia Waite , Edrees H. Rashan , Muhammad Bin Munim , Michael Hemann , View ORCID Profile Matthew G. Vander Heiden doi: https://doi.org/10.64898/2026.09.13.750663 Ryan Elbashir Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ryan Elbashir Keene L. Abbott Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Keene L. Abbott Diya L. Ramesh Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ahmed Ali Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna Shevzov-Zebrun Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna M. Barbeau Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michelle Wu Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abigail P. Ward Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yetis Gultekin Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brian T. Do Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sharanya L Sivanand Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sharanya L Sivanand Azucena Ramos Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tenzin Kunchok Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Millenia Waite Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Edrees H. Rashan Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Muhammad Bin Munim Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Hemann Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthew G. Vander Heiden Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Matthew G. Vander Heiden For correspondence: mvh{at}mit.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions. Competing Interest Statement M.G.V.H. discloses that he is a scientific advisor for Agios Pharmaceuti-cals, Pretzel Therapeutics, Lime Therapeutics, Faeth Therapeutics, Verdandi Therapeutics, S1 Oncology, Droia Ventures, and Auron Thera-peutics. All remaining authors declare no competing interests. Funder Information Declared Howard Hughes Medical Institute , Gilliam Fellowship U.S. National Science Foundation, https://ror.org/021nxhr62 , DGE-1122374 National Institutes of Health, https://ror.org/01cwqze88 , F31CA271787 , T32GM007287 , R35CA242379 Damon Runyon Cancer Research Foundation, https://ror.org/01gd7b947 , DRG-2367-19 Koch Institute Cancer Center Support Grant , P30CA014051 Ludwig Cancer Center National Heart, Lung, and Blood Institute Division of Intramural Research, https://ror.org/023ny1p48 , F30HL156404 MIT Center for Precision Cancer Medicine Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted September 14, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage Ryan Elbashir , Keene L. Abbott , Diya L. Ramesh , Ahmed Ali , Anna Shevzov-Zebrun , Anna M. Barbeau , Michelle Wu , Abigail P. Ward , Yetis Gultekin , Brian T. Do , Sharanya L Sivanand , Azucena Ramos , Tenzin Kunchok , Millenia Waite , Edrees H. Rashan , Muhammad Bin Munim , Michael Hemann , Matthew G. Vander Heiden bioRxiv 2026.09.13.750663; doi: https://doi.org/10.64898/2026.09.13.750663 Share This Article: Copy Citation Tools Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage Ryan Elbashir , Keene L. Abbott , Diya L. Ramesh , Ahmed Ali , Anna Shevzov-Zebrun , Anna M. Barbeau , Michelle Wu , Abigail P. Ward , Yetis Gultekin , Brian T. Do , Sharanya L Sivanand , Azucena Ramos , Tenzin Kunchok , Millenia Waite , Edrees H. Rashan , Muhammad Bin Munim , Michael Hemann , Matthew G. 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