Mitochondrial complex I plus venetoclax in KMT2A-rearranged paediatric AML - a genotype-stratified in vivo PDX result, on a drug whose adult clinical development stopped for toxicity
also called IACS-010759 · complex I inhibition in KMT2A-r AML · OXPHOS inhibitor plus venetoclax
In mice carrying real children's leukaemia samples, a drug that blocks the first step of the mitochondrial energy chain, given together with the approved drug venetoclax, slowed KMT2A-rearranged myeloid leukaemia at both diagnosis and relapse. The difficulty is that the same drug caused nerve damage and dangerous acid build-up when it was tried in adults.
The same thing, for a scientist
A paediatric AML PDX platform of 26 models spanning 14 high-risk genetic subtypes was used to select druggable variants and aberrantly activated pathways in **KMT2A-rearranged AML**, screen them in a three-dimensional coculture model, and test promising compounds in vivo. The combination of **IACS-010759**, a mitochondrial complex I inhibitor, with **venetoclax** reduced AML progression in KMT2A-rearranged PDXs modelling both disease onset and relapse; adding a stromal-targeting drug slowed progression in a resistant model; and the authors conclude that their results strongly support mitochondrial targeting in this genetic AML subtype [E1]. This is the most genotype-specific in vivo metabolic result in the beat. It sits alongside a mechanistic account in which complex I inhibition creates an exploitable dependency through the DELE1-HRI-ATF4 integrated stress response - with MCL-1 rather than BCL-2 as the apoptotic partner [E2] - and against the established finding that OXPHOS inhibition in MLL-rearranged **B-ALL** promotes leukaemia-initiating cell emergence [E3].
Why this is stronger evidence than most of the beat
Three features that most entries here lack:
- Genotype-stratified by design. The KMT2A-rearranged subgroup was the explicit selection unit, not a post hoc slice 1.
- In vivo, in patient-derived material, at two disease states. Onset and relapse models, not a cell-line viability curve 1.
- A partner drug that is already approved and already used in this disease. Venetoclax is in paediatric myeloid practice, so the combination is a realistic protocol rather than a chemistry aspiration.
What it does not have: a published clinical path for the complex I inhibitor. IACS-010759 went into adult trials and its development was constrained by dose-limiting toxicity; this entry does not assert the specifics of that programme because this beat did not retrieve and read the clinical reports, and an unread toxicity claim is exactly the kind of thing this project has been burned by. It is recorded as a known gap and a reading-queue item, not as a fact.
The lineage warning that must travel with this result
This graph's index disease is infant B-lineage KMT2A::AFF1. The published finding in MLL-rearranged B-ALL is that while inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes leukaemia-initiating cell emergence, and that it is hypoxia and glycolysis inhibition, not OXPHOS inhibition, that impairs the initiating compartment 3.
So the two lineages have opposite published recommendations for the same target:
| lineage | intervention | reported effect |
|---|---|---|
| KMT2A-r paediatric AML | complex I inhibitor + venetoclax | reduced progression at onset and relapse 1 |
| MLL-r B-ALL | OXPHOS inhibition | blasts down, leukaemia-initiating cells up 3 |
A clinician reading only the AML result and applying it to an infant with t(4;11) would be making a move the lymphoid literature predicts will reduce the blast count - the visible number - while increasing the compartment that causes relapse. That is the single most dangerous inference available in this beat, and it is why it is written here rather than left implicit.
| target | cell-state-oxphos-dependence |
|---|---|
| molecular target | mitochondrial electron transport chain complex I (NADH:ubiquinone oxidoreductase) |
| agent | IACS-010759 |
| modality | small molecule |
| partner | venetoclax (BCL-2); separately, MCL-1 inhibition in the mechanistic study |
| system | 26 paediatric AML PDX models across 14 high-risk genetic subtypes; KMT2A-rearranged subgroup selected explicitly |
| in vivo result | reduced AML progression in KMT2A-rearranged PDXs modelling both disease onset and relapse; triplet with a stromal-targeting drug slowed progression in a resistant model |
| status | preclinical; no paediatric clinical data |
| reading queue | IACS-010759 adult clinical reports were NOT retrieved by this beat; its toxicity profile is asserted nowhere in this entry and must be read before any proposal is made |
| lineage warning | OXPHOS inhibition in MLL-rearranged B-ALL promotes leukaemia-initiating cell emergence; do not transfer this to infant KMT2A::AFF1 |
- Complex I is required by every oxidative tissue in the body. Inhibitors of this class have produced neurotoxicity and lactic acidosis in adults, and the paediatric therapeutic window is unestablished; a child's developing nervous system is not a reassuring place to find the dose.
- In the lymphoid form of this disease the same intervention has been measured to increase leukaemia-initiating cells while decreasing blasts. The readout a clinician watches - blast count - would improve while the disease's ability to relapse got worse.
- Venetoclax plus a mitochondrial inhibitor is a combination of two agents that both drive apoptosis through the mitochondrion. Tumour lysis syndrome is the predictable acute risk, and this graph already records an MCL-1-plus-venetoclax combination killing 8 of 12 mice from exactly that.
- Resistance in the source study was addressed by adding a third, stromal-targeting drug. A triplet regimen in infants with a disease whose treatment-related mortality already rivals its relapse rate is a serious escalation to propose from preclinical data.
- What is IACS-010759's actual paediatric-relevant toxicity profile? This beat did not read the adult clinical reports and the entry deliberately asserts nothing about them; that reading is the first thing anyone acting on this should do.
- Does complex I inhibition plus a BH3 mimetic reduce or expand the leukaemia-initiating compartment in infant KMT2A::AFF1? The two lineages have opposite published answers and the experiment has never been run in the index disease.
- Is venetoclax or an MCL-1 inhibitor the better apoptotic partner? Two 2026 studies propose each, with different mechanisms, and neither compares them.
- Does the stromal-targeting third agent matter, or was the resistant-model rescue a dose effect? A triplet in an infant needs a much higher bar than 'slowed progression in one model'.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Twenty-six patient-derived xenografts of paediatric AML representing 14 high-risk genetic subtypes were established and shown to recapitulate the immunophenotypic, genomic and transcriptomic profiles of the primary disease; druggable variants and aberrantly activated pathways were selected in KMT2A-rearranged AML and screened in a predictive three-dimensional coculture model; the combination of IACS-010759, a mitochondrial complex I inhibitor, with venetoclax reduced AML progression in KMT2A-rearranged PDXs modelling both disease onset and relapse, and venetoclax plus IACS-010759 plus a stromal-targeting drug slowed AML progression in a resistant model; the authors conclude their preclinical results strongly support mitochondrial targeting in this genetic AML subtype.
Advancing precision therapy in pediatric acute myeloid leukemia through PDX models and mitochondrial targeting. · Da Ros A, Peloso A, Longo G, ..., Pigazzi M · Blood Adv 2026What this evidence cannot show
Abstract read this session; full text not retrieved, so the number of KMT2A-rearranged PDX models in the combination arm, the effect sizes, the survival statistics and the dosing are not known. Paediatric **AML** only - no lymphoid, no infant ALL. 'Reduced AML progression' is not a survival claim and the abstract does not report cures or minimal residual disease. The three-dimensional coculture screen that selected the compounds is described as predictive by the authors and was not independently validated here. No toxicity data in the abstract, and IACS-010759's adult clinical experience was not retrieved by this beat.
Evidence that argues against this (1)
- In MLL-rearranged B-ALL, inhibiting oxidative phosphorylation blunts blast proliferation while promoting leukaemia-initiating cell emergence, so the same class of intervention has an opposite published effect on the relapse-capable compartment in the lymphoid form of this disease. Morris V et al. 2022
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Inhibition of electron transport chain complex I is a synthetic lethal partner for MCL-1 inhibition in AML, synergistically reducing viability in cell lines and PDX samples in vitro and prolonging survival in PDX-bearing mice; mechanistically complex I inhibition activates the integrated stress response with ATF4 activation downstream of the eIF2-alpha kinase HRI, and HRI activation is dependent on the mitochondrial stress messenger DELE1.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia. · Brakefield-Laird L, Budhraja A, Hall PM, ..., Opferman JT · Cell Death Dis 2026What this evidence cannot show
Abstract read this session. KMT2A-motivated rather than KMT2A-demonstrated: the abstract names KMT2A-rearranged AML as the high-risk subtype of interest but reports no KMT2A-stratified analysis and does not state how many models carry the rearrangement. The complex I inhibitor used is not named in the abstract. The apoptotic partner is MCL-1, not venetoclax, so this supports the complex I arm rather than the specific combination in E1.
Evidence that argues against this (1)
- Complex I inhibition and BCL-2 inhibition both converge on mitochondrial apoptosis, so the benefit reported for the venetoclax combination is compatible with simple additivity on one axis rather than with the specific integrated-stress-response priming mechanism. The two results support the same clinical move for potentially different reasons. Da Ros A et al. 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In MLL-rearranged B-ALL, while inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes leukaemia-initiating cell emergence; inhibiting hypoxia and glycolysis instead impairs MLL-rearranged B-ALL leukaemia-initiating cells and provides therapeutic benefit in xenotransplantation systems.
Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells. · Morris V, Wang D, Li Z, ..., Rowe RG · Cell Rep 2022What this evidence cannot show
Abstract read this session; identifiers re-fetched from PubMed rather than copied from sibling entries. Xenotransplantation engraftment is a proxy for leukaemia-initiating capacity. The OXPHOS inhibitor used is not named in the abstract, so extending this to IACS-010759 specifically is an inference about drug class. MLL-rearranged B-ALL as a class; infants are not separately reported.
Evidence that argues against this (1)
- The paediatric AML PDX result is genotype-stratified, in vivo and at two disease states, which is a stronger design than a cell-line comparison; the lineage disagreement is between two well-conducted studies in different diseases rather than between a strong study and a weak one. Da Ros A et al. 2026
mechanistic account of why complex I blockade helps in KMT2A-r AML
- co-occurs with →Venetoclax in KMT2A-rearranged leukemia — the apoptotic partner every other drug needs
the combination tested in KMT2A-rearranged paediatric AML PDXs
reduced progression in PDXs modelling both onset and relapse
complex I blockade attacks the OXPHOS-dependent state
- confers resistance to →KMT2A-rearranged acute lymphoblastic leukaemia
lineage warning: OXPHOS inhibition promotes leukaemia-initiating cell emergence in MLL-rearranged B-ALL