SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.

Yang H, Zingaro VA, Boardman K, Noronha A, Guney E, Xue L, Hoigebazar S, Liu I, Miglani S, Chen S, Vu H, …, Ruggero D · 2026 · Journal of Clinical Investigation · Atlas ID YAN2026

What this study shows

SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy. Silencing SLC15A3 lowered mTORC1 activity and restored sensitivity to 6-mercaptopurine, and the resistant lymphomas, but not the parental tumours, were selectively sensitive to rapamycin in culture and in vivo.

Abstract

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Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model.

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At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Lymphoma cell lines / mouse); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Lymphoma cell lines / mouse
Journal	Journal of Clinical Investigation
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1172/JCI199709 · PMID 42454485 · Free full text (PMC13367966)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	SLC15A3 inhibition; mTORC1 inhibition
Target	mTORC1; SLC15A3 dipeptide transporter; nutrient sensing
Model	Mouse; human lymphoma cell lines
Effect	SLC15A3 imports dipeptides to activate mTORC1, conferring antimetabolite chemoresistance; silencing SLC15A3 restores 6MP sensitivity and resistant lymphomas become selectively rapamycin-sensitive

In the Atlas

Cite this paper

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Yang, H., Zingaro, V. A., Boardman, K., Noronha, A., Guney, E., Xue, L., Hoigebazar, S., Liu, I., Miglani, S., Chen, S., Vu, H., Wen, K. W., Nguyen, H. G., Goodarzi, H., DeBerardinis, R. J., & Ruggero, D. (2026). SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation. Journal of Clinical Investigation. https://doi.org/10.1172/JCI199709

@article{YAN2026,
  author       = {Yang, H. and Zingaro, V. A. and Boardman, K. and Noronha, A. and Guney, E. and Xue, L. and Hoigebazar, S. and Liu, I. and Miglani, S. and Chen, S. and Vu, H. and Wen, K. W. and Nguyen, H. G. and Goodarzi, H. and DeBerardinis, R. J. and Ruggero, D.},
  title        = {{SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation}},
  journal      = {Journal of Clinical Investigation},
  year         = {2026},
  doi          = {10.1172/JCI199709},
  note         = {PMID: 42454485},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record YAN2026) [Data set]. https://mtor-atlas.org/study/YAN2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_YAN2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record YAN2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/YAN2026/},
  doi          = {10.5281/zenodo.22059963}
}

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