Menin's other address list: the same complex that switches on HOXA in blood writes H3K4 methylation onto the CDK inhibitors p27 and p18 in endocrine cells
also called menin-MLL CDK inhibitor axis · menin p27Kip1 p18INK4c · CDKN1B CDKN2C menin
In blood, menin helps switch on genes that keep leukaemia cells immature. In hormone-producing tissue, the same menin machinery switches on two brake genes that stop cells dividing. Losing menin in an islet turns those brakes off, which is why losing menin causes endocrine tumours and not leukaemia.
The same thing, for a scientist
Menin directly regulates the cyclin-dependent kinase inhibitors p27Kip1 (CDKN1B) and p18INK4c (CDKN2C) by recruiting MLL to their promoters and coding regions; loss of either menin or MLL down-regulates both and deregulates cell growth [E1]. In vivo, menin-dependent histone methylation maintains their expression in pancreatic islets: menin associates directly with regions of the p27 and p18 promoters and increases H3 lysine 4 methylation there, and that methylation is reduced at both loci in islet tumours from Men1-mutant mice [E2]. This is the endocrine limb of the same complex whose haematopoietic limb this project studies at HOXA9/MEIS1. It is what makes gene-men1's endocrine-paradox section checkable rather than rhetorical: the paradox is not that one protein has two jobs, it is that the SAME activity - menin-directed MLL H3K4 methylation - has an anti-proliferative output at one address list and a differentiation-blocking output at another.
Two papers, two halves of one mechanism
Milne et al. 2005, human cells 1. Menin activates transcription of CDKN1B and CDKN2C by recruiting MLL to their promoters and coding regions. Loss of function of either MLL or menin down-regulates both and deregulates cell growth. The authors place this as the central mechanism of menin's tumour-suppressor activity.
Karnik et al. 2005, mouse islets in vivo 2. Expression of CDK inhibitors including p27 and p18 is disrupted in mouse islet tumours lacking menin; ChIP shows menin associates directly with regions of the p27 and p18 promoters and increases H3K4 methylation there; and H3K4 methylation at p27 and p18 is reduced in islet tumours from Men1-mutant mice.
The first establishes the recruitment in a tractable system, the second establishes the mark and the direction in the tissue where the disease actually happens.
Why this is the missing half of the endocrine paradox
gene-men1 states the paradox - tumour suppressor in endocrine tissue, required cofactor in KMT2A-rearranged leukaemia - and argues the risk is manageable partly on the grounds that 'menin's parathyroid tumour-suppressor role runs through TGF-beta signalling rather than MLL1'.
That argument is narrower than it reads, and this entry is why. In the islet and in cultured human cells the tumour-suppressor role runs through MLL1, by the same H3K4-methylation activity a menin inhibitor is designed to disrupt 12. The TGF-beta route may well be the parathyroid-specific one; the graph cannot currently cite an experiment that separates them in parathyroid tissue. This is recorded as a tension with an existing claim, not a refutation of it - see the amendment field added to gene-men1 this cycle.
Two pharmacological measurements exist and they disagree in sign - and one of them was already in this graph
A bounded query for CDK-inhibitor readouts under any named pharmacological menin inhibitor returned 2 records, and a three-way query adding an endocrine-tissue clause - run as a CONTROL, expecting zero - returned a third that neither of the first two searches reached.
In the predicted direction. In primary human beta cells, MI-2 plus a TGF-beta inhibitor synergistically drove replication, cooperating through down-regulation of CDKN1A, CDKN1B and CDKN2C 4. That is what this mechanism predicts, in an endocrine tissue, in human cells.
Against. In osteosarcoma lines, MI-503 markedly suppressed H3K4 methylation and increased the expression of p27 3. That is the opposite direction, with the mark and the transcript moving apart in the same cells.
Possible readings of the discrepancy: osteosarcoma is not endocrine and the address list differs; p27 rose as a consequence of arrest and apoptosis (cleaved PARP rose in the same blot) rather than transcriptionally; or the transcriptional model does not generalise beyond the tissues it was built in. Neither study measured H3K4 methylation at a CDK-inhibitor promoter, so the chromatin step of this mechanism has never been tested under drug in any tissue.
The beta-cell result was already in this graph, in mechanism-menin-inhibition-replicates-human-beta-cells-ex-vivo, with the CDKN consequence drawn correctly and in detail. It was not in gene-men1.
| axis | menin -> MLL recruitment -> H3K4 methylation -> CDKN1B (p27Kip1) and CDKN2C (p18INK4c) -> G1 restraint |
|---|---|
| target gene note | Neither gene-cdkn1b nor gene-cdkn2c exists on disk (checked against the full id listing, 2026-09-23), so no edge is written to them. They are named here so a later beat can create them. |
| methylation state not resolved | Both 2005 papers say 'H3 lysine 4 methylation' without resolving me1/me2/me3. This entry therefore links to mark-h3k4me3 as the topic node and states in prose that the state is unresolved. |
| relation to haematopoietic limb | the same complex at a different address list; the haematopoietic limb is HOXA9/MEIS1 and is held in gene-hoxa9, gene-meis1 and the fusion entries |
systems
{
"human_cell_lines_transfection": "recruitment and loss-of-function, PMID 15640349",
"mouse_islet_in_vivo": "ChIP for menin and H3K4 methylation at both promoters; mark reduced in Men1-mutant islet tumours, PMID 16195383",
"pharmacological": "two measurements, opposite signs: CDKN1A/1B/2C DOWN in human beta cells with MI-2 (PMID 32646642); p27 UP in osteosarcoma with MI-503 (PMID 40016386). Neither measured the mark."
}target genes have no entry in this graph
[ "CDKN1B", "CDKN2C" ]
pharmacological measurements
{
"n_in_literature": 2,
"human_beta_cells_MI-2_PMID_32646642": "CDKN1A, CDKN1B and CDKN2C DOWN - predicted direction, endocrine tissue, transcript only",
"osteosarcoma_MI-503_PMID_40016386": "p27 UP while H3K4 methylation DOWN - opposite direction, non-endocrine tissue, protein by Western",
"chromatin_step_under_drug": "NEVER MEASURED in any tissue - no H3K4 methylation readout at CDKN1B or CDKN2C under any menin inhibitor"
}- If menin-MLL H3K4 methylation maintains p27 and p18 in endocrine tissue, then a menin inhibitor is, in those tissues, a CDK-inhibitor-suppressing drug - the exact molecular event that defines the MEN1 tumour-suppressor phenotype, delivered pharmacologically and reversibly.
- The reassuring counter-argument in gene-men1 - that the parathyroid role runs through TGF-beta rather than MLL1 - is doing a lot of work and rests on tissue-specific routing that has not been demonstrated in parathyroid under drug.
- The two pharmacological measurements of this axis disagree in sign - down in human beta cells, up in osteosarcoma. If the osteosarcoma direction is the one that holds in parathyroid, the endocrine risk model in this graph has the sign wrong; if the beta-cell direction holds, the drug suppresses the exact CDK inhibitors whose loss defines the MEN1 tumour phenotype. Both readings are reasons to measure it, and neither is a reason to relax.
- Which methylation state is it? Nobody has repeated the islet ChIP with state-specific H3K4me1/me2/me3 antibodies, and the answer decides whether a menin inhibitor is expected to touch it at all - menin inhibition evicts MLL1 from promoters, and me1 at distal elements would be a different dependency from me3 at the TSS.
- Does a clinical menin inhibitor move p27 or p18 in any tissue? Two records exist in the whole literature for CDK-inhibitor readouts under any named menin inhibitor, neither in an endocrine tissue and neither with revumenib or ziftomenib.
- Is the parathyroid route really TGF-beta rather than MLL1? gene-men1 asserts it and this graph cannot currently cite an experiment that separates the two routes in parathyroid tissue.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c, activating transcription by a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions; loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth.
Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. · Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL · Proc Natl Acad Sci U S A 2005What this evidence cannot show
Cell lines and transfection, per the MeSH terms (Cell Line, Transfection, Luciferase-era promoter work); abstract read, full text not opened. 'Directly regulates' in the abstract is supported by ChIP and loss of function in that paper, but the tissue is not endocrine. NOT CITED anywhere in this corpus before 2026-09-23.
Evidence that argues against this (1)
- A pharmacological menin inhibitor RAISED p27 while suppressing H3K4 methylation in the same cells, which is the opposite direction to this mechanism. Different tissue (osteosarcoma) and an indirect route via arrest and apoptosis cannot be excluded. It is one of only TWO pharmacological measurements of this axis in the literature, and the other one - MI-2 in primary human beta cells, E4 - goes the predicted way, so the two disagree in sign across tissues. Tian S et al. 2025
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In vivo expression of CDK inhibitors including p27 and p18 is disrupted in mouse islet tumours lacking menin; chromatin immunoprecipitation shows menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 of histone H3 associated with these promoters; and H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumours from Men1 mutant mice.
Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. · Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK · Proc Natl Acad Sci U S A 2005What this evidence cannot show
Mouse islet tumours, i.e. a transformed endocrine tissue rather than a normal one, so the reduced mark could be a consequence of transformation as well as a cause. The abstract says 'methylation of lysine 4 in histone H3' without specifying me1, me2 or me3, and 2005-era H3K4 antibodies do not cleanly discriminate the three states, so this entry deliberately does not write H3K4me3. Abstract read, full text not opened. NOT CITED anywhere in this corpus before 2026-09-23.
Evidence that argues against this (1)
- The mark was measured in islet TUMOURS from Men1-mutant mice, so its reduction is confounded with transformation. The graph's reading of this paper as a normal-tissue maintenance mechanism is an extrapolation, and the normal-tissue time course that would justify it has not been reported. Karnik SK et al. 2007
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In osteosarcoma cell lines, the menin inhibitor MI-503 markedly suppressed H3K4 methylation and increased the expression of p27 and cleaved PARP by Western blot, while suppressing Mcl-1 and c-Myc; in a 143B xenograft MI-503 suppressed H3K4 methylation and Ki67 by immunohistochemistry and inhibited tumour growth.
Menin inhibitor MI-503 exhibits potent anti-cancer activity in osteosarcoma. · Tian S, Hao ZY, Xu DH, Wang XZ, Shi CC, Zhang Y · Sci Rep 2025What this evidence cannot show
Osteosarcoma, not an endocrine tissue and not leukaemia; abstract read, full text not opened. 'H3K4 methylation' is not resolved to a methylation state and the abstract does not say whether the p27 rise is transcriptional or a consequence of arrest and apoptosis (cleaved PARP rises in the same blot). MI-503 is a tool compound, not a clinical menin inhibitor. It is one of two pharmacological measurements of this axis; the other (E4, human beta cells) goes the other way. Confidence moderate. Not cited as evidence anywhere in this corpus before 2026-09-23, but it IS named in prose in ana-the-menin-parp-experiment-survives-and-gains-a-rival-rationale, where a bounded 'menin AND PARP' query collected it as a FALSE POSITIVE because the paper reports cleaved PARP as an apoptosis readout. That entry discarded it correctly for its own question and nobody read its p27 result. This record was found by reading a 2-record bounded query result rather than by counting it.
Evidence that argues against this (1)
- Read against the human beta-cell result this may not be a counter-result at all but a tissue difference: in primary human beta cells a menin-MLL inhibitor LOWERED CDKN1A, CDKN1B and CDKN2C, the direction this mechanism predicts. Two pharmacological measurements, two tissues, two signs. Pahlavanneshan S et al. 2020
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In primary human pancreatic beta cells, the menin-MLL interaction inhibitor MI-2 combined with TGF-beta signalling inhibitors synergistically increased ex vivo replication without affecting insulin production, cooperating through down-regulation of the cell-cycle inhibitors CDKN1A, CDKN1B and CDKN2C.
Combined inhibition of menin-MLL interaction and TGF-beta signaling induces replication of human pancreatic beta cells. · Pahlavanneshan S, Behmanesh M, Oropeza D, Furuyama K, Tahamtani Y, Basiri M, Herrera PL, Baharvand H · Eur J Cell Biol 2020What this evidence cannot show
Ex vivo human donor islets over days; MI-2 is an early tool compound weaker than MI-463/MI-503 and is not a clinical molecule; transcript-level only, NO chromatin readout, so this confirms the transcriptional direction and says nothing about H3K4 methylation. Abstract read, full text not opened. Already cited twice in this corpus, in mechanism-menin-inhibition-replicates-human-beta-cells-ex-vivo and concept-menin-inhibition-is-an-active-therapeutic-hypothesis, and the first of those draws the same conclusion; this entry adds the pairing with the discordant osteosarcoma result.
Evidence that argues against this (1)
- The same experiment with a different compound in a different tissue gave the opposite sign - p27 UP under MI-503 in osteosarcoma while H3K4 methylation fell. Until one laboratory runs both tissues side by side, the direction of the pharmacological effect on this axis is unsettled. Tian S et al. 2025
menin recruits MLL to CDKN1B and CDKN2C and raises H3K4 methylation there (PMIDs 15640349, 16195383)
- depends on →KMT2A / MLL1 — the gene that breaks
MLL is the enzyme menin recruits to these promoters
topic link only - the 2005 papers do not resolve the methylation state
the molecular content of the brake that the beta cell releases on purpose
the endocrine arm a menin inhibitor would be expected to disrupt; never measured under drug
the same adaptor activity at a different address list with the opposite cell-state output
the module whose tissue distribution is being measured
the endocrine limb of the hypothesis
- ← depends onThe endocrine cell's resting state is an actively maintained G1 restraint, and menin is what maintains it
the molecular mechanism that maintains the state