Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug
also called Armstrong Lab · Dana-Farber Pediatric Oncology · DFCI menin programme
This Boston group showed that KMT2A-rearranged leukemia is a distinct disease and then did the mouse and patient-sample work that made menin inhibitors real drugs. They are the most established competitor and the most valuable potential ally in this space at the same time.
The same thing, for a scientist
Armstrong's laboratory, in the Department of Pediatric Oncology at Dana-Farber Cancer Institute with the Division of Hematology/Oncology at Boston Children's Hospital and Harvard Medical School, defined KMT2A-rearranged leukemia as a transcriptionally distinct entity (2001), established DOT1L and then menin as actionable dependencies, generated the preclinical package for VTP-50469 that Syndax developed into revumenib, and co-authored both the first-in-human revumenib trial report and the paper identifying MEN1 interface mutations as the clinical resistance mechanism. Andrei Krivtsov was first author on the pivotal VTP-50469 preclinical paper from the same department.
What they own that the Iqbal Lab does not1 deeper
Three things, and none of them is cheap to replicate.
A validated PDX bank of KMT2A-rearranged AML and ALL with in-vivo drug response data. The VTP-50469 paper ran patient-derived xenografts of both lineages and reported mice engrafted with KMT2A-r ALL remaining disease-free for more than a year after treatment 2. Building that resource from scratch is a multi-year, multi-hundred-thousand-dollar undertaking, and it is the resource any new interface-disruption idea has to pass through.
A direct line into the clinical trial and its correlative samples. Armstrong is an author on the first-in-human revumenib paper (NCT04065399) 3 and on the resistance paper that read MEN1 mutations out of patients who relapsed on that trial 4. On-treatment and at-relapse patient material from a registrational menin-inhibitor trial is not obtainable by any route other than being inside that consortium.
A twenty-year publication claim on the biology. The 2001 Nature Genetics paper establishing that MLL-translocated ALL is a separate disease with its own expression signature is theirs 1. Anything the lab writes about KMT2A-r as a distinct entity stands on that result.
Competitor or collaborator?
Honestly: competitor on mechanism, collaborator only on something they are not already doing. If the Iqbal Lab proposes to characterise menin-KMT2A interface biology or menin-inhibitor resistance, it is entering a contest against a group with the PDX bank, the trial samples, in-house structural biology (Fischer lab at DFCI is on the resistance paper), a base-editor screening platform, and industry funding. The 2023 resistance paper already used an unbiased base-editor screen to enumerate resistance mutations before they appeared in patients 4; that is the obvious next experiment for a small lab, and it is done.
The realistic partnering angle is orthogonal: bring something they do not have. Candidates are (a) non-menin obligate interfaces in KMT2A::AFF1 that are not on their roadmap, (b) infant-specific biology, since the trial population is dominated by adults and older children, and (c) computational interface prediction across fusion families, which is cheap for us and low priority for them.
What they actually found, briefly
- KMT2A/MLL-translocated ALL has a gene-expression profile consistent with an early haematopoietic progenitor expressing select multilineage markers and individual HOX genes, and separates cleanly from conventional ALL and AML 1.
- VTP-50469, an orally bioavailable menin-MLL inhibitor, displaces menin from protein complexes, reduces MLL chromatin occupancy at select genes, and eradicates disease in KMT2A-r PDX models 2.
- Revumenib produced a 30% CR/CRh rate in relapsed/refractory KMT2A-r or NPM1-mutant acute leukaemia, with asymptomatic QT prolongation as the only dose-limiting toxicity 3.
- Somatic MEN1 mutations at the drug-menin interface cause acquired clinical resistance; they impair small-molecule binding but preserve MLL1 binding 4. This is the single most important caveat for the whole interface-disruption thesis.
| group | Armstrong Laboratory (Scott A. Armstrong); Andrei V. Krivtsov |
|---|---|
| institution | Department of Pediatric Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Boston Children's Hospital; Harvard Medical School, Boston MA, USA (affiliation as printed on PubMed-indexed papers through 2023) |
| focus | Chromatin dependencies of KMT2A-rearranged and NPM1-mutant acute leukaemia; DOT1L and menin as therapeutic targets; preclinical-to-clinical translation of menin inhibitors; resistance genetics |
| partnering angle | Do not compete on menin. Approach with an orthogonal asset: a non-menin obligate interface in KMT2A::AFF1, infant-specific biology their adult-weighted trial population cannot address, or a computational cross-family interface map. Their PDX bank and on-treatment trial samples are the reciprocal ask. |
| relationship | competitor-first, collaborator-if-orthogonal |
key papers — the numbers behind the chart
[
{
"title": "MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia",
"year": 2001,
"venue": "Nature Genetics",
"pmid": "11731795",
"doi": "10.1038/ng765"
},
{
"title": "A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia",
"year": 2019,
"venue": "Cancer Cell",
"pmid": "31821784",
"doi": "10.1016/j.ccell.2019.11.001"
},
{
"title": "The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia",
"year": 2023,
"venue": "Nature",
"pmid": "36922593",
"doi": "10.1038/s41586-023-05812-3"
},
{
"title": "MEN1 mutations mediate clinical resistance to menin inhibition",
"year": 2023,
"venue": "Nature",
"pmid": "36922589",
"doi": "10.1038/s41586-023-05755-9"
}
]leverage they hold
[ "KMT2A-r ALL and AML PDX bank with menin-inhibitor response data", "on-treatment and relapse samples from NCT04065399", "base-editor resistance screening platform", "industry co-development relationship with Syndax" ]
- Any interface-disruption programme the lab starts will be benchmarked against this group's data; a result they can produce faster makes the lab's work redundant on arrival.
- Their own resistance paper is the strongest published argument that obligate-partner interfaces are not durable targets, which cuts directly at the lab's central hypothesis.
- Collaborating means their PDX bank and their framing; a small lab contributing one assay to a DFCI-led paper gets a middle authorship and loses independent claim to the idea.
- Has the group already screened non-menin KMT2A::AFF1 interfaces and found nothing worth publishing? A negative result sitting in their drawer would change the lab's priorities more than any positive result in the literature.
- Are their KMT2A::AFF1 PDX models predominantly from older children and adults rather than infants? If so, infant-specific fetal-origin biology is genuinely uncovered ground even inside the best-resourced lab in the field.
- Krivtsov's institutional affiliation after 2019 was not verified here; if he has moved to industry the academic-collaboration route through him is closed.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Armstrong's group established that MLL/KMT2A-translocated ALL has a distinct gene-expression profile consistent with an early haematopoietic progenitor with select multilineage markers and individual HOX genes, and constitutes a separate disease entity.
MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia · Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ · Nature Genetics 2001What this evidence cannot show
Microarray-era study on bulk samples; the 'distinct entity' framing has since been complicated by single-cell work showing heterogeneity within KMT2A-r cases and by lineage switching. Affiliation at the time was Dana-Farber Cancer Institute, Boston. Note the author list already contains Rob Pieters and Monique den Boer in Rotterdam, so a Boston-Netherlands axis predates the current landscape.
Evidence that argues against this (1)
- The distinct-profile result is a 2002 classification on early microarrays and a small cohort, and this graph's own mechanism beat records the structure it misses: within t(4;11) alone, patients divide into HOXA-high and HOXA-low groups. A profile distinct at the disease level is compatible with substantial heterogeneity inside it, which matters because menin-inhibitor response is expected to track the HOXA axis. Nature Genetics 2002
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Krivtsov and Armstrong generated the preclinical package for the menin-MLL inhibitor VTP-50469 (the compound behind revumenib), showing selective activity in KMT2A-r cell lines and durable disease-free survival in KMT2A-r ALL and AML patient-derived xenografts.
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia · Krivtsov AV, Evans K, Gadrey JY, et al., Lock RB, Armstrong SA · Cancer Cell 2019What this evidence cannot show
Industry-entangled: Syndax and CGM Pharma co-authors, so the compound-selection framing is not a neutral read of the target space. PDX cure data in immunodeficient mice systematically overstate durability relative to patients. The paper also shows the work was run jointly with Richard Lock's group at Children's Cancer Institute, UNSW Sydney, a separate and less obvious partnering target for PDX work.
Evidence that argues against this (1)
- Closes this entry's third open question, and adds a second, more recent disclosure. The entry states that 'Krivtsov's institutional affiliation after 2019 was not verified here; if he has moved to industry the academic-collaboration route through him is closed.' He has not. On a 2025 Cancer Research paper, Andrei V. Krivtsov is affiliated to the Department of Pediatric Oncology, Dana-Farber Cancer Institute and the Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School -- the same institutions as in 2019 -- with Scott A. Armstrong listed at the same two. The academic route is open. The same paper's disclosure section adds a second patent: 'S.A. Armstrong reports personal fees from Accent Therapeutics, AstraZeneca, C4 Therapeutics, Hyku Therapeutics, Neomorph, Inc., and Stelexis Therapeutics and grants from Syndax Pharmaceuticals and Janssen Biotech outside the submitted work; in addition, S.A. Armstrong has a patent for "Menin inhibition in NPM1 AML" issued.' So the Syndax and Janssen research funding is current as of 2025, not historical, and there are at least two issued or filed patents on menin inhibition with this investigator named. Caveats: author affiliations on one paper establish where someone was credentialed at submission, not their present appointment, and this paper is on p53 biology rather than leukaemia chromatin, so it is evidence of institutional affiliation only. Read: author affiliations and disclosure section of the PubMed record; abstract read, not full text. Klemm N et al. 2025
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Armstrong is a co-author on the first-in-human phase 1 revumenib trial (NCT04065399), which reported a 30% CR/CRh rate in relapsed/refractory KMT2A-rearranged or NPM1-mutant acute leukaemia with asymptomatic QT prolongation as the only dose-limiting toxicity.
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia · Issa GC, Aldoss I, DiPersio J, et al., Armstrong SA, Stein EM · Nature 2023What this evidence cannot show
Single-arm phase 1 in a heavily pretreated population; CR/CRh is a surrogate and the efficacy analysis population is a subset of those treated. Several authors are Syndax employees.
Evidence that argues against this (1)
- The 30% is the phase 1 dose-escalation figure and the registration-enabling phase 2 did not reproduce it: AUGMENT-101 phase 2 reported CR+CRh of 22.8% in 57 efficacy-evaluable patients from 94 treated. Both numbers are correctly attributed in this graph, but a collaboration entry citing the higher one without the later one overstates what the programme has shown. Dose-escalation response rates in enriched, heavily selected early cohorts routinely exceed the registration result. Journal of Clinical Oncology 2025
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The group identified somatic MEN1 mutations at the revumenib-menin interface as the mechanism of acquired clinical resistance, confirmed in xenograft models and by an unbiased base-editor screen; the mutants impair drug binding while preserving the natural MLL1 interaction.
MEN1 mutations mediate clinical resistance to menin inhibition · Perner F, Stein EM, Wenge DV, et al., Levine RL, Armstrong SA, Cai SF · Nature 2023What this evidence cannot show
Relapsed/refractory single-agent setting; frequency in frontline or combination use is unknown. This is also the paper that makes the 'obligate partner interface is a durable target' claim harder to defend, and it was published by the group that would be the lab's main competitor on that claim.
Evidence that argues against this (1)
- A documented conflict this entry does not record, stated from the paper's own competing-interests section and nothing else. The competing-interests statement of the resistance paper itself reads, for S.A.A.: 'has been a consultant and/or shareholder for Vitae/Allergan Pharmaceuticals, Neomorph, Inc., Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, and Accent Therapeutics. S.A.A. has received research support from Janssen, and Syndax and is an inventor on a patent related to Menin Inhibition WO/2017/132398A1.' Vitae Pharmaceuticals is the originator of VTP-50469, the compound behind revumenib, and Janssen and Syndax are the sponsors of two of the four clinical menin inhibitors. Three things follow that a collaboration plan should account for, none of which is a criticism of anyone. (1) There is an issued patent estate on menin inhibition with this investigator named, so any chemical matter a joint project generated at the menin interface enters a space with a prior claim. (2) Research support from both Syndax and Janssen means the group is inside, not outside, the commercial menin programme; the entry's 'competitor-first, collaborator-if-orthogonal' classification is right but its reason is understated. (3) It reinforces the entry's own advice: bring something orthogonal to menin, because menin itself is encumbered. Caveat: a declared interest is a disclosure, not a finding about conduct, and disclosure lists change between papers. Read: the competing-interests section of the paper, retrieved from the PubMed record 2026-09-18; abstract read, not full text. Perner F et al. 2023
established menin dependency and drove the preclinical inhibitor work
Counter-evidence (competing-interests statement, PMID 36922589): named inventor on menin-inhibition patent WO/2017/132398A1 plus an issued 'Menin inhibition in NPM1 AML' patent, with current research support from Syndax and Janssen -- the menin interface is encumbered IP for this collaboration
Counter-evidence (competing interests, PMID 36922589 and PMID 40163352): issued menin-inhibition patents plus current Syndax and Janssen research support -- freedom-to-operate, not only priority, is the reason to route around menin
generated the preclinical VTP-50469 package that established menin as a drug target and identified MEN1 interface mutations as the clinical resistance mechanism
preclinical origin (VTP-50469) and co-authorship of the first-in-human trial NCT04065399
- related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
defined KMT2A-translocated ALL as a transcriptionally distinct entity (2001) and cured KMT2A-r ALL PDX models with menin inhibition
classified as competitor on menin mechanism and resistance
Bernt's DOT1L dependency work was performed in the Armstrong group before she established her own programme