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Peer-reviewedCC BY-NC-NDBlood red cells & iron

Exosomal miR-26a delivery increases erythroid expansion in models of Diamond-Blackfan anemia.

  • Jaqueline Mercado1
  • Mallika Saxena1
  • Gavin M Traber1
  • Ryan S Sathianathen1
  • Bertil Glader1
  • Paraic Kenny2
  • Kathleen M Sakamoto1
  • Mark C Wilkes1,2
  1. 1Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA.
  2. 2Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI.
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Abstract

Diamond-Blackfan anemia (DBA) is a pure red blood cell aplasia with a predisposition toward cancer. In DBA erythroid progenitors, nemo-like kinase (NLK) is activated, and mammalian target of rapamycin complex 1 (mTORC1) activity is suppressed. Systemic leucine administration high enough to hyperstimulate mTORC1 improves erythroid expansion in patients and animal models of DBA. However, leucine at such high doses significantly increases malignant transformation of nonerythroid cells upon exposure to carcinogens, heightening cancer risk in these patients. Here we show that exosomal delivery of miR-26a restores basal mTORC1 activity in erythroid progenitors by targeting the NLK transcript for degradation. miR-26a delivery does not hyperstimulate mTORC1, but removal of NLK-mediated mTORC1 suppression primes erythroid cells for mTORC1 hyperstimulation at a 10-fold lower systemic dose of leucine. Delivery of exosomal miR-26a supports optimal mTORC1 hyperstimulation and erythroid expansion with the administration of a leucine dose that does not increase the risk of transformation in nonerythroid cells, thus offering a safe, novel, and effective treatment strategy for increasing erythropoiesis in DBA.

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Cite

BibTeXRIS
BibTeX
@article{mercado2026exosomal,
  title = {{Exosomal miR-26a delivery increases erythroid expansion in models of Diamond-Blackfan anemia.}},
  author = {Jaqueline Mercado and Mallika Saxena and Gavin M Traber and Ryan S Sathianathen and Bertil Glader and Paraic Kenny and Kathleen M Sakamoto and Mark C Wilkes},
  journal = {Blood red cells \& iron},
  year = {2026},
  month = jul,
  doi = {10.1016/j.brci.2026.100104},
  url = {https://europepmc.org/article/MED/42924381},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Exosomal miR-26a delivery increases erythroid expansion in models of Diamond-Blackfan anemia.
AU  - Jaqueline Mercado
AU  - Mallika Saxena
AU  - Gavin M Traber
AU  - Ryan S Sathianathen
AU  - Bertil Glader
AU  - Paraic Kenny
AU  - Kathleen M Sakamoto
AU  - Mark C Wilkes
PY  - 2026
DA  - 2026/07/21
JO  - Blood red cells & iron
DO  - 10.1016/j.brci.2026.100104
UR  - https://europepmc.org/article/MED/42924381
AB  - Diamond-Blackfan anemia (DBA) is a pure red blood cell aplasia with a predisposition toward cancer. In DBA erythroid progenitors, nemo-like kinase (NLK) is activated, and mammalian target of rapamycin complex 1 (mTORC1) activity is suppressed. Systemic leucine administration high enough to hyperstimulate mTORC1 improves erythroid expansion in patients and animal models of DBA. However, leucine at such high doses significantly increases malignant transformation of nonerythroid cells upon exposure to carcinogens, heightening cancer risk in these patients. Here we show that exosomal delivery of miR-26a restores basal mTORC1 activity in erythroid progenitors by targeting the NLK transcript for degradation. miR-26a delivery does not hyperstimulate mTORC1, but removal of NLK-mediated mTORC1 suppression primes erythroid cells for mTORC1 hyperstimulation at a 10-fold lower systemic dose of leucine. Delivery of exosomal miR-26a supports optimal mTORC1 hyperstimulation and erythroid expansion with the administration of a leucine dose that does not increase the risk of transformation in nonerythroid cells, thus offering a safe, novel, and effective treatment strategy for increasing erythropoiesis in DBA.
SN  - 3050-5984
ER  -