Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
also called targetable steps KMT2A · compensation map · resistance by step · menin DOT1L BET CDK9 ENL comparison
Walking through the fusion's six steps, only two are both necessary and selective enough to drug: the menin clamp and the histone mark. For each, we now know what the cell does to get around the drug — and in every case the escape route is already published.
The same thing, for a scientist
Step-by-step: DNA targeting (step 1) is required but not fusion-selective; the menin/LEDGF clamp (step 2) is required, selective and clinically validated; SEC/elongation (step 3) is the mechanism but is built from common-essential machinery; DOT1L/H3K79me2 (step 4) is selective but kinetically slow; the output program (step 5) is internally redundant; the phenotype (step 6) is the readout. A head-to-head panel confirms the selectivity split: menin and DOT1L inhibitors act specifically on KMT2A-fused lines and induce differentiation, whereas BET, DHODH and CDK9 inhibitors act well beyond KMT2A fusions and mainly induce apoptosis. Every compensation route is documented: MEN1 gatekeeper mutations and non-genetic pre-existing resistance for menin; ABCB1 efflux for DOT1L; WNT/beta-catenin-driven MYC restoration for BET; an ENL point mutation for ENL inhibitors.
The selectivity split, measured head to head
Across a large cell-line panel, menin-MLL and DOT1L inhibitors act very specifically on KMT2A-fused lines, whereas BET, DHODH and P-TEFb/CDK9 inhibitors have strong effects well beyond KMT2A fusions. Menin, DOT1L and DHODH inhibitors induced significant differentiation; BET and CDK9 inhibitors primarily induced apoptosis 1.
This is the cleanest single piece of evidence that step 2 and step 4 are the selective nodes and step 3 is not, and it is why the graph grades CDK9 as 'the mechanism but not the target' (see mechanism-sec-elongation-hijack).
Step 2 — menin/LEDGF clamp: rate-limiting, selective, and the escape routes are known3 deeper
Genetic escape. Somatic MEN1 mutations at the revumenib-menin interface arise in patients with acquired resistance, conserved across xenografts and confirmed by an unbiased base-editor screen. The mutants attenuate drug-target binding but not the interaction with the natural ligand MLL1, and they prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To the authors' knowledge this is the first chromatin-targeting drug shown to select escape mutants in patients 2.
Non-genetic and pre-existing escape — the more worrying one. Heavily pretreated KMT2A::AFF1 ALL samples were markedly less menin-inhibitor-sensitive than earlier samples from the same patients, with no prior menin-inhibitor exposure. Transcriptomics showed sustained on-target efficacy in the resistant cells — resistance downstream of target engagement. Emergent comutations including RAS-pathway and TP53 were present but neither was sufficient to induce resistance in vitro; KMT2C/D downregulation was implicated in one patient 3.
Read that carefully: it means a menin inhibitor can be working molecularly and failing clinically, in the exact disease this grant addresses, in patients who have never seen the drug class. This is the most direct published threat to the menin-interface hypothesis in the graph, and it is not a resistance mechanism a better inhibitor would fix.
What pre-empts it. Two combinations have published support. The IKAROS degrader mezigdomide synergises with menin inhibitors including in MEN1-mutant models, and with VTP-50469 it increased survival and prevented and overcame MEN1 mutations 4. And KAT7 interacts with menin and the KMT2A complex; combined KAT6/KAT7 catalytic inhibition (PF-9363) rapidly evicts the fusion protein from chromatin, overcomes primary resistance, and KAT7 remains a targetable dependency in acquired genetic and non-genetic resistance to menin inhibition 5.
The strategic inference: because resistance can occur downstream of engagement, the winning design is not a better single-interface inhibitor but a combination that increases the completeness of complex eviction — which is also what the dose biology predicts (mechanism-hoxa9-meis1-dose-requirement).
Step 4 — DOT1L: selective, slow, and resistance via efflux
Pinometostat had modest single-agent activity in 51 adults, with only 2 complete remissions, both in t(11;19) 6, and treatment-emergent resistance in five KMT2A-rearranged lines arose without target mutation — via ABCB1/P-glycoprotein efflux in KOPN-8 and by an unresolved efflux-independent route in NOMO-1 7. A transporter-mediated escape is chemotype-linked rather than target-linked, so it would affect any structurally similar agent and would be invisible to target sequencing.
Step 3 — BET and CDK9: not selective, and BET resistance is unusually well characterised
Two independent groups published converging BET-resistance mechanisms in the same Nature issue, which makes this among the most solid resistance findings in the field.
A chromatin-focused RNAi screen in MLL-AF9;Nras-G12D AML found PRC2 suppression promotes BET-inhibitor resistance (the opposite direction to other contexts), not by directly altering BRD4-dependent transcripts but by remodelling pathways that restore MYC transcription; resistant human leukemias were uniformly characterised by rapid restoration of MYC transcription via activation and recruitment of WNT signalling components and a focal MYC enhancer 8.
Independently, MLL-AF9-immortalised murine HSPC clones resistant to I-BET were cross-resistant to JQ1 and to genetic BET knockdown, not efflux- or metabolism-mediated, and the resistance emerged from leukaemia stem cells; chromatin-bound BRD4 was globally reduced while Myc expression remained unaltered, and resistance was in part a consequence of increased WNT/beta-catenin signalling, with negative regulation of WNT restoring I-BET sensitivity in vitro and in vivo 9.
Note the second paper's detail: resistance arose from leukaemia stem cells and was not drug-efflux-based, so it is a cell-state escape. That is the same category as the non-genetic menin resistance in 3, and it suggests a general principle for this disease: the dominant escape route is cell-state plasticity, not target mutation.
ENL/YEATS — an emerging node with its escape mutation already found
Chemical matter exists at two levels of maturity. SR-0813 is an ENL/AF9 YEATS-domain inhibitor (IC50 25 nM, from a ~300,000-compound screen) alongside a first-in-class ENL PROTAC SR-1114, and ENL YEATS inhibition is sufficient to selectively suppress ENL target genes 10. TDI-11055 is a potent, orally bioavailable ENL inhibitor that displaces ENL from chromatin by blocking YEATS-acylated-histone binding, is active in KMT2A-rearranged and NPM1-mutant lines and primary samples, rapidly decreases chromatin occupancy, impairs elongation, induces differentiation and blocks progression in CDX and PDX models — and a CRISPR-Cas9 mutagenesis screen already uncovered an ENL mutation conferring resistance, validating on-target activity and pre-announcing the escape route 11.
That last point is a model of good practice: the resistance mutation was found before the clinic. The lab should ask the same question of any interface it pursues — run the base-editor or mutagenesis screen early, as was done for MEN1 2.
| chain | mechanism-kmt2a-fusion-causal-chain |
|---|---|
| dominant escape category | cell-state plasticity rather than target mutation |
| design recommendation | run a base-editor or CRISPR mutagenesis resistance screen against any new interface BEFORE clinical translation, as was done for MEN1 and for ENL/TDI-11055 |
steps — the numbers behind the chart
[
{
"step": 1,
"node": "mechanism-fusion-dna-targeting-cxxc-athooks",
"required": true,
"fusion_selective": false,
"rate_limiting": false,
"verdict": "deprioritise — shared with wild-type KMT2A and the CXXC family",
"compensation": "AT-hook/CXXC redundancy; methylome shift redirects targeting"
},
{
"step": 2,
"node": "mechanism-menin-ledgf-chromatin-tethering",
"required": true,
"fusion_selective": true,
"rate_limiting": true,
"verdict": "best node; clinically validated",
"compensation": "MEN1 gatekeeper mutations; non-genetic pre-existing resistance downstream of engagement; residual IBM2/LEDGF and AT-hook retention"
},
{
"step": 3,
"node": "mechanism-sec-elongation-hijack",
"required": true,
"fusion_selective": false,
"rate_limiting": true,
"verdict": "the mechanism, not the target — common-essential machinery",
"compensation": "AEP recruited by alternative routes (KMT2A::AFDN precedent); WNT/beta-catenin MYC restoration under BET pressure"
},
{
"step": 4,
"node": "mechanism-dot1l-h3k79-methylation",
"required": true,
"fusion_selective": true,
"rate_limiting": "partially — kinetically slow",
"verdict": "combination partner, not backbone",
"compensation": "ABCB1/P-gp efflux; unresolved efflux-independent routes; mark removed only by replicative dilution"
},
{
"step": 5,
"node": "mechanism-hoxa9-meis1-output-program",
"required": true,
"fusion_selective": false,
"rate_limiting": false,
"verdict": "buffered; no single output gene is necessary",
"compensation": "Hoxa-cluster redundancy; network feed-forward relay; MCL1 co-activation defeats BCL2 inhibition"
},
{
"step": 6,
"node": "mechanism-self-renewal-differentiation-block",
"required": true,
"fusion_selective": false,
"rate_limiting": false,
"verdict": "the readout; differentiation syndrome is the mechanism-linked cost",
"compensation": "lineage switching instead of terminal maturation"
}
]emerging nodes
[
{
"target": "ENL/MLLT1 YEATS",
"probes": [
"SR-0813",
"SR-1114 PROTAC",
"TDI-11055"
],
"resistance_already_found": true
},
{
"target": "gene-kat7 / KAT6",
"probe": "PF-9363",
"role": "overcomes primary and acquired menin-inhibitor resistance; evicts fusion from chromatin"
},
{
"target": "IKAROS (mezigdomide)",
"role": "prevents and overcomes MEN1 mutations in combination"
},
{
"target": "gene-cbx8 chromodomain",
"probe": "SW2_110A",
"role": "required for fusion-driven activation; viable knockout in normal blood"
},
{
"target": "BCOR-MLL-AF9 interface",
"role": "required in vivo; largely absent from published target maps"
},
{
"target": "KMT2B/MLL2",
"role": "better-supported wild-type dependency than KMT2A itself"
}
]- Menin: MEN1 gatekeeper mutations preserve MLL1 binding and block drug-induced eviction, restarting the program with the drug still bound; and non-genetic resistance occurs in treatment-naive-to-the-class KMT2A::AFF1 patients with target engagement intact.
- DOT1L: ABCB1/P-gp efflux resistance is chemotype-linked, would affect structurally similar successors, and is invisible to target sequencing.
- BET: two independent studies show resistance via WNT/beta-catenin-driven MYC restoration emerging from leukaemia stem cells, not efflux — a cell-state escape that cross-resists genetic BET depletion.
- CDK9/SEC: common-essential machinery; kills without differentiating, so cytotoxicity in screens systematically over-ranks these agents.
- KAT7 and PAF1c, the two most promising eviction-enhancing partners, are both DepMap common-essential — the combinations that work best mechanistically carry the worst therapeutic-index risk.
- Differentiation syndrome scales with efficacy for every differentiation-inducing agent in this list, so success and toxicity cannot be separated by dose alone.
- Why are heavily pretreated KMT2A::AFF1 samples menin-inhibitor-resistant with preserved target engagement? This is the single most important unexplained observation for this project. A candidate answer worth testing: the resistant cells have shifted to a chromatin/cell state in which the output program no longer depends on fusion occupancy.
- Is the dominant escape route in this disease cell-state plasticity rather than mutation? Three independent lines (non-genetic menin resistance, BET resistance emerging from LSCs, WNT-mediated MYC restoration) point that way. If true, single-agent interface disruption is structurally insufficient and the correct programme is interface disruption plus a state-locking agent.
- Which combination should be prioritised for infant KMT2A::AFF1: menin + DOT1L (phenocopies degradation), menin + KAT6/KAT7 (evicts fusion, overcomes primary resistance), or menin + venetoclax (differentiation plus apoptosis)? None has been compared head to head in an infant ALL model.
- Does WNT/beta-catenin activation also mediate menin-inhibitor resistance, as it does BET resistance? Nobody appears to have looked, and WNT inhibitors exist.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a head-to-head cell-line panel, menin-MLL and DOT1L inhibitors acted very specifically on KMT2A-fused lines whereas BET, DHODH and P-TEFb/CDK9 inhibitors had strong effects well beyond KMT2A fusions; menin, DOT1L and DHODH inhibitors induced significant differentiation while BET and CDK9 inhibitors primarily induced apoptosis.
Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia · Brzezinka K, Nevedomskaya E, Lesche R, et al. (Stresemann C, senior author) · Journal of Hematology & Oncology 12(1):66 2019What this evidence cannot show
Industry cell-line panel with no in-vivo confirmation; compound-specific potency and off-target profiles confound class-level conclusions.
Evidence that argues against this (1)
- The differentiation-blockage framing of this panel is an AML story and does not transfer to KMT2A-rearranged ALL. Adriaanse et al. compared revumenib in KMT2A-r ALL and AML in vitro and found ALL samples undergo rapid, dose-dependent leukaemic cell death while AML responses are much slower and proceed through myeloid differentiation. A cell-line panel scored on differentiation therefore measures different things in the two lineages, and 'relieving the differentiation block' is not the mechanism of benefit in the ALL setting this project cares about. Adriaanse FRS et al. 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Somatic MEN1 mutations at the revumenib-menin interface mediate clinical resistance to menin inhibition, conserved across xenografts and confirmed by an unbiased base-editor screen; the mutants attenuate drug-target binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin.
MEN1 mutations mediate clinical resistance to menin inhibition · Perner F, Stein EM, Wenge DV, et al. (Cai SF, senior author) · Nature 615(7954):913-919 2023What this evidence cannot show
Acquired resistance in a relapsed/refractory population under single-agent pressure; frequency in frontline or combination settings is unknown. Specific residue lists commonly quoted should be read from the paper's figures rather than asserted.
Evidence that argues against this (1)
- MEN1 interface mutation is not the only clinical route, and possibly not the commonest. Mahdavi et al. found heavily pretreated KMT2A::AFF1 ALL samples markedly less menin-inhibitor-sensitive than earlier samples from the same patients despite no prior class exposure, with transcriptomics showing sustained on-target drug effect in the resistant cells. Resistance that leaves the target engaged is not explained by a rate-limiting-step model and is not addressed by a next-generation binder. Mahdavi L et al. 2025
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Heavily pretreated KMT2A::AFF1 ALL samples were markedly less menin-inhibitor-sensitive than earlier samples from the same patients despite no prior menin-inhibitor exposure, with transcriptomics showing sustained on-target efficacy in resistant cells; emergent RAS-pathway and TP53 comutations were present but neither was sufficient to induce resistance in vitro, and KMT2C/D downregulation was implicated in one patient.
Upfront menin-inhibitor resistance in multiply pretreated leukemias · Mahdavi L, Alikarami F, Goodrow H, et al. (Bernt KM, senior author) · Experimental Hematology 153:105268 2025What this evidence cannot show
Two serial patients plus five PDX models — small n, and 'sustained on-target efficacy' is inferred from transcriptional signatures rather than from direct chromatin-occupancy measurement in the resistant cells. Nevertheless it is in exactly the fusion and disease this project targets, which is why it is graded as the most direct published threat.
Evidence that argues against this (1)
- Resistance arising with no menin-inhibitor exposure and with on-target repression preserved is the entry's most important observation, and the emergent RAS and TP53 lesions it also reports offer a complete alternative explanation. Until the two are separated, this cannot be read as evidence for a rate-limiting-step account. Nature 2023
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The IKAROS degrader mezigdomide is effective alone and synergises with menin inhibition in preclinical models of KMT2A-rearranged and NPM1-mutant AML, including MEN1-mutant models; combined with VTP-50469 it increased survival and prevented and overcame MEN1 mutations.
Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML · Bourgeois W, Cutler JA, Aubrey BJ, et al. (Armstrong SA, senior author) · Blood 143(15):1513-1527 2024What this evidence cannot show
Preclinical only; AML models rather than infant KMT2A::AFF1 ALL. 'Prevented MEN1 mutations' is an observation in mouse models under drug pressure, and IKAROS degradation has its own immunological consequences in a paediatric patient.
Evidence that argues against this (1)
- Mezigdomide combination data are preclinical. The clinical bound for the class it is combined with is AUGMENT-101: CR+CRh 22.8% in 57 efficacy-evaluable of 94 treated KMT2A-r patients. Preclinical prevention of MEN1 mutations has not yet been shown to move that number, so the compensation argument should not be carried at clinical confidence. Issa GC et al. 2024
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
KAT7 interacts with menin and the KMT2A complex; combined catalytic KAT6/KAT7 inhibition (PF-9363) rapidly evicts the KMT2A fusion protein from chromatin, enhances menin-inhibitor efficacy and overcomes primary resistance, and KAT7 remains an important targetable dependency in both genetic and non-genetic acquired resistance to menin inhibition.
Catalytic Inhibition of KAT6/KAT7 Enhances the Efficacy and Overcomes Primary and Acquired Resistance to Menin Inhibitors in MLL Leukemia · Gordon SJV, Perner F, MacPherson L, et al. (Armstrong SA, Dawson MA, senior authors) · Cancer Discovery 15(10):2117-2138 2025What this evidence cannot show
Preclinical; KAT7/KAT6 are broadly important acetyltransferases, so the therapeutic index of chronic dual inhibition in children is unestablished. KAT7 is DepMap common-essential, which is a structural concern rather than a chemistry one.
Evidence that argues against this (1)
- Same limitation: KAT6/KAT7 catalytic inhibition rescuing menin-inhibitor resistance is cell-line and xenograft data. Against it stands the fact that the one directly analogous epigenetic combination that reached patients - DOT1L inhibition with pinometostat - reduced H3K79 methylation as designed and produced two complete remissions in 51 adults. On-target pharmacodynamics in this pathway has repeatedly failed to convert into clinical benefit. Stein EM et al. 2018
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Pinometostat in 51 adults with acute leukemia reduced H3K79 methylation as intended but produced only 2 complete remissions, both in t(11;19), with efficacy as a single agent described as modest; the MTD was not reached.
The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia · Stein EM, Garcia-Manero G, Rizzieri DA, et al. (Tallman MS, senior author) · Blood 131(24):2661-2669 2018What this evidence cannot show
Adults only; n=2 responders cannot support a partner-specific efficacy claim. Continuous IV infusion regimen is not a viable long-term dosing posture.
Evidence that argues against this (2)
- The trial did not reach its maximum tolerated dose, so it did not test the drug at the limit of what patients can take. That matters for the inference drawn here: modest single-agent activity with unreached MTD and a continuous-infusion schedule is consistent with inadequate exposure as well as with the pathway being non-limiting. Both complete remissions occurring in t(11;19) also hints at partner-specific sensitivity the trial was not designed to detect. Blood 2018
- Non-canonical H3K79me2-dependent pathways promote survival of KMT2A-rearranged leukaemia, which gives a third reading: the drug removed the mark and left the pathways that matter. Reduced methylation with preserved survival is a mechanistic result, not only a pharmacological disappointment. eLife 2021
- E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Treatment-emergent resistance to pinometostat in five KMT2A-rearranged lines arose without DOT1L target mutation; KOPN-8 resistance was mediated by ABCB1/P-glycoprotein efflux upregulation and NOMO-1 resistance was efflux-independent with an unresolved mechanism.
Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia · Campbell CT, Haladyna JN, Drubin DA, et al. (Bernt KM, Daigle SR, senior authors) · Molecular Cancer Therapeutics 16(8):1669-1679 2017What this evidence cannot show
Prolonged in-vitro selection strongly favours efflux mechanisms over patient-relevant biology; no patient resistance data exist because the drug did not reach efficacy.
Evidence that argues against this (1)
- Efflux-mediated resistance in KOPN-8 is a pharmacological escape that says nothing about the pathway, and NOMO-1's unresolved mechanism is unresolved. Citing "no DOT1L target mutation" as informative assumes target mutation is the alternative to be excluded; for an enzyme inhibitor with a large active site it is not the expected route. Blood 2018
- E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In MLL-AF9;Nras-G12D AML, a chromatin-focused RNAi screen showed PRC2 suppression promotes BET-inhibitor resistance by remodelling pathways that restore MYC transcription rather than by altering BRD4-dependent transcripts; resistant human leukemias were uniformly characterised by rapid restoration of MYC transcription via activation and recruitment of WNT signalling components and a focal MYC enhancer.
Transcriptional plasticity promotes primary and acquired resistance to BET inhibition · Rathert P, Roth M, Neumann T, et al. (Vakoc CR, Zuber J, senior authors) · Nature 525(7570):543-547 2015What this evidence cannot show
Compound MLL-AF9;NrasG12D mouse model plus human lines; the PRC2-suppression result is context-specific and runs opposite to PRC2's requirement in the untreated leukemia, which complicates any PRC2-directed combination.
Evidence that argues against this (1)
- This is murine MLL-AF9 in the myeloid compartment and the index disease of this graph is human infant KMT2A::AFF1 B-lymphoid leukaemia. The two differ in the partner, in the lineage, in the cell of origin and — on this beat's own evidence — in HOXA output, since infant t(4;11) is HOXA-LOW while the mouse models are built on HOXA activation. Retroviral MLL-AF9 also expresses the fusion far above the single rearranged allele a patient carries. The result is also about BET inhibition, where MYC is the proximate output. Restoration of MYC transcription is the escape route specific to that target, and generalising it to a compensation principle for menin inhibition assumes a shared bottleneck the entry has not shown. Oncofusion knowledge graph (internal analysis) 2026
- E9established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
MLL-AF9-immortalised murine HSPC clones resistant to I-BET were cross-resistant to JQ1 and to genetic BET knockdown, were not efflux- or metabolism-mediated, and emerged from leukaemia stem cells; chromatin-bound BRD4 was globally reduced while Myc expression remained unaltered, resistance was in part a consequence of increased WNT/beta-catenin signalling, and negative regulation of WNT restored I-BET sensitivity in vitro and in vivo.
BET inhibitor resistance emerges from leukaemia stem cells · Fong CY, Gilan O, Lam EYN, et al. (Dawson MA, senior author) · Nature 525(7570):538-542 2015What this evidence cannot show
Murine MLL-AF9 immortalised clones under in-vitro selection; the convergence with the independent WNT finding in the same journal issue is what makes this unusually strong, but neither study is in KMT2A::AFF1 lymphoid disease.
Evidence that argues against this (1)
- These are murine HSPC clones selected under prolonged I-BET exposure in culture, which is a strong and unphysiological selection. Globally reduced chromatin-bound BRD4 with unaltered Myc is an interesting decoupling and is a property of the surviving clones, not a demonstration that the same state pre-exists in patients. Oncofusion knowledge graph (internal analysis) 2026
- E10strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
A screen of approximately 300,000 compounds yielded SR-0813, an ENL/AF9 YEATS-domain inhibitor with IC50 25 nM, plus the first-in-class ENL PROTAC SR-1114; ENL YEATS inhibition is sufficient to selectively suppress ENL target genes.
Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia · Garnar-Wortzel L, Bishop TR, Kitamura S, et al. (Erb MA, senior author) · ACS Central Science 7(5):815-830 2021What this evidence cannot show
In-vitro and cellular chemical-probe characterisation; SR-0813 inhibits both ENL and AF9 YEATS domains, so paralogue-selective biology cannot be attributed from it. No in-vivo efficacy data.
Evidence that argues against this (1)
- Chemical-probe potency is not a dependency argument. In the one head-to-head panel cited in this entry, inhibitors acting on general elongation machinery had strong effects well beyond KMT2A-fusion lines, so an ENL YEATS inhibitor's activity needs a non-KMT2A comparator before it is counted as a fusion-selective vulnerability; and treatment-emergent resistance to an epigenetic inhibitor in this disease has arisen through ABCB1 efflux with no target mutation at all (Campbell 2017), which no target-engagement measurement would detect. Campbell CT et al. 2017
- E11strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
TDI-11055, a potent orally bioavailable ENL inhibitor, displaces ENL from chromatin by blocking YEATS-acylated-histone binding, is active in KMT2A-rearranged and NPM1-mutant lines and primary patient samples, rapidly decreases chromatin occupancy of ENL complexes, impairs elongation, induces differentiation and blocks progression in CDX and PDX models; a CRISPR-Cas9 mutagenesis screen uncovered an ENL mutation conferring TDI-11055 resistance, validating on-target activity.
Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia · Liu Y, Li Q, Alikarami F, et al. (Wan L, senior author) · Cancer Discovery 12(11):2684-2709 2022What this evidence cannot show
Preclinical; AML-focused, so activity in infant KMT2A::AFF1 ALL is inferred from line and primary-sample data rather than demonstrated in that disease. The identified resistance mutation pre-announces the escape route but its clinical frequency is unknown.
Evidence that argues against this (1)
- TDI-11055 is preclinical and blocks the YEATS acyl-histone interaction, which removes ENL's chromatin binding and not ENL's scaffolding. This graph records ENL PERSISTING at oncoprotein target loci after both the fusion and menin are undetectable, so a reader-pocket inhibitor may leave in place the part of ENL that matters. Journal of Clinical Oncology 2025
- ← analogous toFault trees, minimal cut sets and common-cause failure — reliability engineering on a buffered oncogenic program
compensation as redundancy, formalised
- ← related toCBFB::MYH11 (CBFbeta-SMMHC), inv(16)(p13;q22)
Sufficiency bound (Castilla 1999, PMID 10508507): Cbfb-MYH11 knock-in chimeric mice are only PREDISPOSED to acute myelomonocytic leukaemia and required ENU mutagenesis to develop it, so the embryonic block does not show the fusion alone drives disease.
- ← analogous toFault trees, minimal cut sets and common-cause failure — reliability engineering on a buffered oncogenic program
reliability engineering's minimal cut set applied to a buffered transcriptional program
- related to →Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133
which step is worth blocking, and what compensates
- confers resistance to →Revumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor
Counter-evidence (Mahdavi 2025, PMID 41027490): resistance in multiply pretreated KMT2A::AFF1 ALL arose with sustained on-target drug effect and without prior menin-inhibitor exposure - a failure mode outside the rate-limiting-step model.
Scope counter (Adriaanse 2024, PMID 38892207): the differentiation-blockage framing is an AML observation; KMT2A-r ALL dies rapidly under menin inhibition rather than differentiating.
modifier, not a step - which links are rate-limiting, and the bite-back map