Th17 cell - the mature CD4 T-helper subset whose differentiation and maintenance require MENIN, which makes it the clearest published on-target normal-tissue liability of the menin interface
also called T helper 17 cell · IL-17-producing CD4 T cell · RORgt+ CD4 T cell · Th17
Th17 cells are a kind of helper T cell that produces the signal IL-17 and defends mucosal surfaces, and they also drive several inflammatory diseases. This graph needs them because menin - the protein the leading KMT2A drugs block - is required to make Th17 cells and to keep them made.
The same thing, for a scientist
The vocabulary gap was named by Q69, which found that RTF1's only measured haematopoietic cell-type requirement is in Th17 cells and declined to force it onto `cell-type-early-t-precursor` or `cell-type-clp`. Writing the node turned up something the dispatch did not anticipate and that is more load-bearing than the RTF1 result: **Menin is required for Th17 differentiation and maintenance**. Menin-deficient T cells do not efficiently differentiate into Th17 cells while Th1 and Th2 differentiation remains intact in vitro; Menin deficiency attenuates Th17-induced airway inflammation; in differentiating Th17 cells Menin binds the Il17a locus directly and is required there for permissive histone modifications and for recruitment of the RNA polymerase II complex; and although Menin also binds the Rorc locus it is dispensable for Rorc induction and instead required to **maintain** Rorc expression in already-differentiated Th17 cells [E1]. That is a Trithorax-complex function of menin in a normal, non-malignant, non-KMT2A-rearranged cell, and it is the same protein surface that revumenib, ziftomenib, bleximenib and enzomenib occupy. The second strand is the one the gap was reported for: RTF1 deficiency disrupts Th17 differentiation while leaving regulatory T cells unaffected, through RTF1's histone-modification domain and H2B monoubiquitination, phenocopied by loss of the H2Bub1 E3 ligase subunit RNF40 [E2]. Menin's T-cell role is not confined to Th17 - in primary human peripheral-blood T cells, c-Myb, GATA-3, Menin and MLL form a complex controlling GATA-3 expression and Th2 maturation [E3] - which sharpens rather than softens the liability.
Why this node is load-bearing for the menin-interface hypothesis
This project's central bet is that the menin-KMT2A interface is a tractable and reasonably selective target. The usual counter-argument is resistance (MEN1 M327I and friends). This node supplies a different one: a documented, mechanistically detailed, Trithorax-dependent requirement for menin in a normal immune cell that the drug will also reach.
The detail matters, because it is not a bulk-expression observation. Menin binds the Il17a locus directly in differentiating Th17 cells and is required there for the permissive marks and for Pol II complex recruitment; it binds Rorc and is required to maintain, not to induce, its expression 1. That is the same read-write function on the same kind of locus that this graph attributes to menin in leukaemia. Pharmacologically displacing menin from KMT2A should, on that mechanism, also displace it from these loci.
What the literature does not contain is any measurement of Th17 cells, IL-17 or RORgt in a patient on a menin inhibitor. That is an absence of testing, not a negative result, and it is written here as an open question rather than as reassurance.
The RTF1 result that the gap was reported for
RTF1 is a PAF1-complex-associated factor and is broadly expressed. Its one measured haematopoietic cell-type requirement is here: Rtf1 deficiency disrupts Th17 differentiation while leaving regulatory T cells unaffected; the mechanism is RTF1-facilitated H2B monoubiquitination requiring its histone modification domain, and impaired Th17 differentiation is also seen in cells lacking RNF40, a subunit of the H2Bub1 E3 ligase that physically interacts with RTF1 2.
The selectivity within the cell type is the informative part, as gene-rtf1 already says: a general elongation factor would be expected to hit both CD4 fates, and it hits one. That argues the requirement is programme-specific rather than housekeeping - the same logic this graph applies to the fusion's own target selectivity.
RTF1's relevance here is doubled by the fact that the gene was reached through this graph's PAF1-complex interest, and PAF1C is one of the complexes the KMT2A fusion machinery runs through.
Menin in T helper cells is broader than Th17, and that is worse not better
In primary human peripheral-blood CD4 T cells, c-Myb and GATA-3 form a transcriptionally active complex essential for Th2 development; immunoprecipitation shows that complex contains Menin and MLL, MLL recruitment is associated with Th2 memory formation, and silencing c-Myb decreases H3K4 methylation and H3K9 acetylation at the GATA-3 locus 3.
So the menin exposure in T-helper biology is not a single-subset curiosity. Note the tension with 1, which reports Th1 and Th2 differentiation intact in Menin-deficient mouse T cells: one is mouse differentiation in vitro and the other is human primary T cells with an emphasis on memory maintenance, and 'differentiation intact' and 'maintenance impaired' are compatible. A 2024 review consolidates the picture across memory Th2 maintenance, Th17 differentiation and maintenance, CD4 T-cell senescence and effector CD8 survival, and explicitly raises inhibiting menin as a strategy for inflammatory disease 4 - which is the same pharmacology this graph is pursuing for leukaemia, pointed at a different organ.
What a Th17 cell is, operationally
A mature effector CD4 T-helper subset defined by production of IL-17A (and IL-17F, IL-22), by the lineage transcription factor RORgt encoded by RORC, and by differentiation conditions involving TGF-beta with IL-6 and IL-23 for stabilisation. It is a terminal effector fate, not a progenitor, which is precisely why cell-type-early-t-precursor - a thymic precursor - was the wrong node and was deliberately not used.
It is also not a leukaemic cell in this graph. Every claim in this entry is about normal immunity, and the entry's value to a leukaemia graph is exactly that: it is where two of the graph's central proteins do a job in a bystander tissue.
| ontology | CL:0000899 |
|---|---|
| ontology note | CL:0000899 is 'T-helper 17 cell'. cell-type-early-t-precursor (a thymic precursor) and cell-type-clp were explicitly considered and rejected by Q69 as wrong answers for this claim. |
| position in hierarchy | a terminal effector fate of the mature CD4 T-cell compartment, downstream of thymic development - NOT a progenitor, which is why the graph's early-T-precursor node was the wrong home for this claim |
| differentiation conditions | TGF-beta with IL-6; IL-23 for stabilisation of the effector programme |
| shown for fusion | NO for the fusion, but NOT a bare 'nobody has looked' for the protein: menin's Th17 requirement is established genetically in normal mouse T cells (PMID 25136117). What has never been done is the pharmacological version - no menin inhibitor has been tested for an effect on Th17 differentiation or maintenance, and no trial of revumenib, ziftomenib, bleximenib or enzomenib reports Th17, IL-17 or RORgt. |
| why this node exists | Q69 found RTF1's only measured haematopoietic cell-type requirement to be in Th17 cells and recorded it as a vocabulary gap rather than approximating to cell-type-early-t-precursor or cell-type-clp. Writing the node surfaced the menin result, which the dispatch did not anticipate and which is the more load-bearing of the two. |
markers
[ "CD4+", "IL-17A+ (also IL-17F, IL-22)", "RORgt (RORC) as lineage transcription factor", "IL-23R+ for the pathogenic/stabilised state", "CCR6+" ]
genes in this graph with a measured requirement here
[
{
"gene": "gene-men1",
"requirement": "differentiation AND maintenance; binds Il17a directly and is required for permissive marks and Pol II recruitment there; binds Rorc and is required to MAINTAIN rather than induce it",
"pmid": "25136117",
"system": "mouse, genetic"
},
{
"gene": "gene-rtf1",
"requirement": "differentiation; via H2B monoubiquitination through its histone modification domain, phenocopied by RNF40 loss; Treg explicitly unaffected",
"pmid": "40073106",
"system": "murine/primary T-cell differentiation"
}
]bounded absence
{
"date": "2026-09-21",
"tool": "NCBI esearch db=pubmed",
"query": "(menin[tiab] OR Men1[tiab] OR MLL1[tiab] OR KMT2A[tiab]) AND (Th17[tiab] OR Th2[tiab] OR \"T helper\"[tiab])",
"count": 11,
"on_topic_after_title_check": 5,
"what_is_absent": "no record in this query pairs a named menin INHIBITOR with a Th17 or T-helper readout; the drug-name arm of the question returns nothing on topic. Per rule 72 the drug names that would have to be searched are revumenib, ziftomenib, bleximenib, enzomenib, VTP-50469, MI-503, MI-538, MI-2-2, plus 'menin inhibitor', 'menin inhibitors' and 'menin inhibition' as three distinct strings.",
"bound": "titles and abstracts only; supporting figures not searched (rule 80)"
}- This is the strongest normal-tissue liability of the menin interface currently in this graph. Menin is required for Th17 differentiation and maintenance in normal T cells through direct occupancy of Il17a and maintenance of Rorc - the same read-write function the drugs are designed to block - so a menin inhibitor is predicted to be an IL-17-axis immunosuppressant.
- Th17 cells defend mucosal surfaces against Candida and extracellular bacteria; the human genetics of IL-17 pathway loss is chronic mucocutaneous candidiasis. An infant on prolonged menin inhibition after cytotoxic induction is exactly the host in whom that would matter, and no trial measures it.
- The liability is invisible to current trial reporting. Without Th17 or IL-17 measurements, an on-target immune effect appears only as scattered infectious adverse events that will be attributed to the backbone chemotherapy.
- A separate field is proposing menin inhibition AS an anti-inflammatory therapy for excessive T-cell activation. When two fields pursue the same pharmacology for opposite purposes, the immunosuppression is not a hypothetical side effect - somebody is counting on it.
- If the Th2 arm holds in humans, the exposure extends to memory Th2 maintenance, which touches durable immunity rather than only acute defence - and memory compartments are slower to show a deficit and slower to recover.
- Does a menin inhibitor reproduce the Menin-deficiency Th17 phenotype? The requirement is established genetically and has never been tested pharmacologically. Revumenib or VTP-50469 in a standard in vitro Th17 differentiation assay, scoring IL-17A and RORgt, is a one-week experiment on drugs already in children, and it would convert an inference into a measurement.
- Has any menin-inhibitor trial measured T-cell subsets? No published trial reports Th17 counts, IL-17 or RORgt. Infections and immune events in those trials are reported as adverse events with no immunophenotype behind them, so an on-target Th17 effect would currently be invisible.
- Is the menin requirement in T cells KMT2A-dependent? Menin has KMT2A-independent functions, and the Th17 work is a Menin-deficiency phenotype. If the Il17a requirement runs through the MBM pocket it is a direct drug liability; if it runs through a different menin surface it is not. A menin-KMT2A-interface point mutant in T cells separates them.
- Do Th17 and Th2 exposures differ between mouse and human? Mouse Menin loss leaves Th1/Th2 differentiation intact while a human primary T-cell complex containing Menin and MLL controls Th2 memory. Which applies in a treated child is unresolved and is the difference between a narrow and a broad immune liability.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
IN MICE, Menin, a component of the Trithorax group complex, is critical for Th17 cell differentiation and maintenance: Menin-deficient T cells do not efficiently differentiate into Th17 cells while Th1 and Th2 differentiation remain intact in vitro, Menin deficiency attenuates Th17-induced airway inflammation, in differentiating Th17 cells Menin binds the Il17a locus directly and is required for deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex, and although Menin binds the Rorc locus it is dispensable for Rorc induction but required to maintain Rorc expression in differentiated Th17 cells.
Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells. · Watanabe Y, Onodera A, Kanai U, Ichikawa T, Obata-Ninomiya K, Wada T, et al., Nakayama T · Proc Natl Acad Sci U S A 2014What this evidence cannot show
Murine, genetic (Menin deficiency) rather than pharmacological, and in vitro differentiation plus an airway inflammation model - no menin inhibitor is used anywhere in it, so it does not establish that occupying the MBM pocket reproduces the phenotype. Menin has KMT2A-independent functions, so a Menin-deficiency phenotype is not automatically a menin-KMT2A-interface phenotype, and the entry's inference to drug liability is an inference. Nothing here is human. Read: abstract only. NOT PREVIOUSLY CITED ANYWHERE IN THIS GRAPH - checked with scripts/check-citation-reuse.py on 2026-09-21.
Evidence that argues against this (1)
- The same gene points the other way for a different CD4 fate in a HUMAN system, which means 'Menin deficiency spares Th1 and Th2' does not travel. In primary human peripheral-blood CD4 T cells the c-Myb/GATA-3 complex essential for Th2 development contains Menin and MLL, and MLL recruitment into that complex accompanies Th2 memory formation. Mouse in vitro differentiation being intact is compatible with human memory maintenance being menin-dependent, but it means the subset-selectivity of the menin requirement in T cells is unsettled - and an unsettled selectivity is a wider liability, not a narrower one. Read: abstract only. Nakata Y et al. 2010
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
IN MURINE/PRIMARY T-CELL DIFFERENTIATION in an inflammatory-disease context, Rtf1 deficiency disrupts the differentiation of Th17 cells while leaving regulatory T cells unaffected; mechanistically RTF1 facilitates histone H2B monoubiquitination, which requires its histone modification domain, and impaired Th17 differentiation is also observed in cells lacking RNF40, a subunit of the H2Bub1 E3 ligase known to interact physically with RTF1.
RTF1 mediates epigenetic control of Th17 cell differentiation via H2B monoubiquitination. · Galan C, Lu G, Gill R, Li D, Liu Y, Huh JR, Hang S · J Immunol 2025What this evidence cannot show
T-cell differentiation cultures framed around ulcerative colitis risk genetics - not leukaemia, not B-lineage, not KMT2A-rearranged, and no measurement in any haematopoietic stem or progenitor cell. The Treg-spared comparison is the informative control and is what makes the requirement look programme-specific rather than housekeeping. Already cited in gene-rtf1. Read: abstract only.
Evidence that argues against this (1)
- The H2Bub1 route and the menin/Trithorax route are two different epigenetic requirements reported for the same cell fate, and neither paper tests the other's pathway. Menin's requirement in Th17 runs through direct binding at Il17a with permissive marks and Pol II recruitment, and through maintenance of Rorc; RTF1's runs through H2B monoubiquitination with RNF40. If both are real, Th17 differentiation has at least two independently essential chromatin inputs, and attributing a Th17 defect to either one without testing the other is unsupported. Read: abstract only. Watanabe Y et al. 2014
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
IN PRIMARY HUMAN PERIPHERAL-BLOOD CD4 T CELLS, c-Myb and GATA-3 are core elements of a transcriptionally active complex essential for Th2 development and maintenance; immunoprecipitation shows that the c-Myb/GATA-3 complex contains Menin and MLL, MLL recruitment into the c-Myb-GATA-3-Menin complex is associated with formation of Th2 memory cells, and silencing c-Myb significantly decreases H3K4 methylation and H3K9 acetylation at the GATA-3 locus in developing Th2 and CD4 effector/memory cells.
c-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development. · Nakata Y, Brignier AC, Jin S, Shen Y, Rudnick SI, Sugita M, Gewirtz AM · Blood 2010What this evidence cannot show
This is Th2, not Th17, and is included to bound the claim that the menin requirement in T cells is Th17-specific. It is a co-immunoprecipitation and knockdown study in primary human T cells; menin is not itself perturbed, so its requirement is inferred from complex membership rather than demonstrated by loss of function. 'MLL' here is the wild-type protein in a normal cell, not a fusion. Read: abstract only.
Evidence that argues against this (1)
- Direct genetic loss of Menin in mouse T cells leaves Th1 and Th2 differentiation intact in vitro while abolishing Th17, which is the loss-of-function test this Th2 result does not perform. Complex membership by co-immunoprecipitation is weaker evidence of requirement than a differentiation failure in a knockout, so the Th2 exposure should be held at lower confidence than the Th17 one until a menin loss-of-function experiment is done in human Th2 cells. Read: abstract only. Watanabe Y et al. 2014
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review
A 2024 review consolidates the reported roles of Menin in T-cell differentiation and function across memory Th2 maintenance, Th17 differentiation and maintenance, CD4 T-cell senescence and effector CD8 T-cell survival, and explicitly raises inhibiting Menin activity as a potential strategy for inflammatory diseases associated with excessive T-cell activation.
Roles of Menin in T cell differentiation and function: Current knowledge and perspectives. · Zhou P, Liu W, Ma J · Immunology 2024What this evidence cannot show
A narrative review, included only as a map of how wide the menin-in-T-cell literature is; no primary claim in this entry rests on it. Its therapeutic framing - menin inhibition as an anti-inflammatory strategy - is the mirror image of this graph's framing and is a proposal, not a result. Read: abstract only.
Evidence that argues against this (1)
- A review proposing menin inhibition for inflammatory disease is describing the same pharmacology this graph pursues for leukaemia, which means the immunosuppressive consequence is the intended effect in one field and an unmeasured side effect in the other. Neither framing is supported by a clinical measurement: no published menin-inhibitor trial reports Th17 counts, IL-17 or RORgt. The primary Th17 requirement is genetic, not pharmacological. Read: abstract only. Watanabe Y et al. 2014
RESIDENCY: in differentiating Th17 cells Menin binds the Il17a locus directly and is required there for permissive histone modifications and Pol II complex recruitment; it also binds the Rorc locus. Chromatin occupancy in the cell is the basis for this edge
REQUIREMENT, separate from the residency edge: Menin-deficient T cells do not efficiently differentiate into Th17 while Th1 and Th2 remain intact in vitro, and Menin is required to MAINTAIN Rorc expression in differentiated Th17 cells
Rtf1 deficiency disrupts Th17 differentiation while leaving Treg unaffected, via H2B monoubiquitination through its histone modification domain; the Treg-spared control is what makes it programme-specific. The cell type Q69 named as missing vocabulary
PREDICTED ON-TARGET LIABILITY, not a measured one: menin is required for Th17 differentiation and maintenance in normal T cells through the same read-write function the drug blocks, and no published menin-inhibitor trial reports Th17, IL-17 or RORgt
the nearest wrong answer, deliberately not used by Q69: a thymic precursor is not a mature CD4 effector fate, and forcing the RTF1 result onto it would have asserted a developmental stage the source does not