IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells
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
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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
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| 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 | 2026-10-01 |
| Source | DOI 10.1182/blood.2026034181 · PMID 42752592 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
Energy & cellular stress activates AMPKStrongest evidence: M (Molecular — cells, biochemistry, structure) · settled in the literature · Status: Proposed
plausible in people, not shown directly
XIA2011 (crystal structure and biochemistry of mammalian AMPK) demonstrates that AMP binding to the gamma regulatory domain promotes phosphorylation and protects against dephosphorylation, and that ADP binds too. GWI2008 and ZHO2001 show…
People in the Atlas
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Leukaemia researcher at Heidelberg University and first author of the 2026 study showing that the enzyme IDH3 keeps acute myeloid leukaemia stem cells metabolically fit and resistant to venetoclax
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Studies metabolic vulnerabilities of leukemia stem cells; senior author on a 2026 Blood paper on IDH3, citrate and mTORC1 in AML stem cell drug resistance
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Group leader at ETH Zurich's Institute of Molecular Systems Biology who develops mass spectrometry methods to measure hundreds of metabolites at once, used in many collaborations on cell metabolism
More: 24 other authors
No profile yet: Mönnig M, Aroua N, Besiridou E, Schmidt V, Müller K, Renders S, Schulte F, Pouya A, Waclawiczek A, Leppä AM, Stumpf K, Sohn M, Depke D, Wuchter P, Karpova D, Donato E, Bonig H, Andresen C, Büttner M, Poschet G, Hübschmann D, Sauer T, Trumpp A, Müller-Tidow C
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Topics
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 | IDH3A knockdown (shRNA); BCL2 inhibition with venetoclax |
| Target | IDH3A-citrate-AMPK-mTORC1 axis |
| Model | Human AML patient samples, bone marrow organoids, xenograft mice |
| Effect | IDH3A loss raised intracellular citrate, activated AMPK and suppressed mTORC1 and translation, sensitising leukemic stem cells to venetoclax. |
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