IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells

Demir A, Mönnig M, Aroua N, Besiridou E, Schmidt V, Raffel S · 2026 · Blood · Atlas ID DEM2026

What this study shows

IDH3A loss in AML leukemic stem cells reduces TCA cycle flux and raises intracellular citrate, activating AMPK and suppressing mTORC1 (lowering translation), which sensitizes cells to BCL2 inhibition by venetoclax - nominating the IDH3A-citrate-AMPK-mTORC1 axis as a target to overcome venetoclax/azacitidine resistance.

Abstract

ShowHide

Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human AML patient samples, bone marrow organoids, xenograft mice) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Human AML patient samples, bone marrow organoids, xenograft mice
Journal	Blood
Year	2026
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1182/blood.2026034181 · PMID 42752592

Cite this paper

ShowHide

Demir, A., Mönnig, M., Aroua, N., Besiridou, E., Schmidt, V., & Raffel, S. (2026). IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells. Blood. https://doi.org/10.1182/blood.2026034181

@article{DEM2026,
  author       = {Demir, A. and Mönnig, M. and Aroua, N. and Besiridou, E. and Schmidt, V. and Raffel, S.},
  title        = {{IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells}},
  journal      = {Blood},
  year         = {2026},
  doi          = {10.1182/blood.2026034181},
  note         = {PMID: 42752592},
}

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 DEM2026) [Data set]. https://mtor-atlas.org/study/DEM2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_DEM2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record DEM2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/DEM2026/},
  doi          = {10.5281/zenodo.22059963}
}