Menin inhibition makes adult human beta cells divide in a dish - the hardest thing in beta-cell biology
also called MI-2 human beta cell replication · menin inhibitor TGF-beta beta cell · human islet proliferation screen
Adult human insulin-making cells almost never divide, which is why diabetes is hard to cure. A menin-blocking molecule, combined with a second drug, got them to replicate without losing their ability to make insulin.
The same thing, for a scientist
Two studies from the same group put menin inhibition into the human beta-cell regeneration literature. In a screen of selected small molecules on human pancreatic beta cells, the menin-MLL interaction inhibitor **MI-2** and TGF-beta signalling inhibitors (SB431542, LY2157299 or LY364947) **synergistically** increased ex vivo replication of human beta cells, without loss of insulin production, cooperating through down-regulation of the cell-cycle inhibitors CDKN1A, CDKN2C and CDKN1B [E1]. A companion methods paper, using a refined rat primary islet monolayer culture, independently found MI-2 among the molecules that significantly induced beta-cell replication [E2]. Adult human beta-cell replication is notoriously refractory, so a reproducible hit here is not a trivial result.
Why the CDKN result matters for the safety reading
The cooperation runs through down-regulation of CDKN1A (p21), CDKN1B (p27) and CDKN2C (p18) 1. Those are exactly the cyclin-dependent kinase inhibitors that menin normally maintains, and p18/p27 loss is the documented route by which Men1 deficiency drives neuroendocrine tumours in mice. So the mechanism of the therapeutic effect in human islets and the mechanism of neoplasia in Men1-null mice are the same molecular step, distinguished only by degree and duration. This is the clearest single illustration in this beat of why the benefit and the harm cannot be separated pharmacologically - only temporally.
What is not shown
Both studies are ex vivo, both use MI-2 (an early tool compound, weaker than MI-463/MI-503 and far from a clinical molecule), neither has an in-vivo human-relevant arm, and neither follows the replicated cells long enough to ask whether they stop. The human work is donor islets in culture for days. No clinical menin inhibitor has been tested on human islets at all.
| compound | MI-2 (menin-MLL interaction inhibitor) |
|---|---|
| insulin production | preserved |
| clinical compounds tested | none |
partner drugs
[ "SB431542", "LY2157299 (galunisertib)", "LY364947", "indolactam V (PKC activator)" ]
tissue
[ "human donor islets", "rat primary islets" ]
effectors
[ "CDKN1A", "CDKN1B", "CDKN2C" ]
- The therapeutic effect and the MEN1 tumour mechanism are the same step - loss of p21/p27/p18 restraint - so this result is simultaneously the best evidence of benefit and the best evidence that the benefit is the front end of the harm.
- The human effect needs a second drug (TGF-beta inhibition) that is not part of any menin-inhibitor regimen, so single-agent human relevance is unproven.
- None of the clinical menin inhibitors has ever been put on a human islet; the entire human-tissue evidence base for this beat rests on tool compounds.
- Do revumenib, ziftomenib or bleximenib replicate human beta cells ex vivo, and at what multiple of the concentration needed to displace KMT2A?
- Do the replicated human beta cells exit the cycle when the compound is washed out?
- Is the CDKN1A/1B/2C down-regulation detectable in a treated patient - for example in circulating islet-derived cell-free DNA methylation?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The menin-MLL inhibitor MI-2 synergises with TGF-beta inhibitors to increase ex vivo replication of human pancreatic beta cells without impairing insulin production, via down-regulation of 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, et al. · European Journal of Cell Biology 2020What this evidence cannot show
Ex vivo human donor islets, small molecule panel screen, days of culture; MI-2 is an early low-potency tool compound; the synergy requires a second drug that is not part of any clinical menin-inhibitor regimen; no long-term fate of the replicated cells.
Evidence that argues against this (1)
- The cell-cycle inhibitors down-regulated here (p21, p27, p18) are the same ones whose loss collaborates with Men1 deficiency to produce neuroendocrine tumours in mice, so the mechanism of the therapeutic effect is the mechanism of the tumour. Harding B et al. 2009
- E2weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
In a refined rat primary islet monolayer screen, the menin inhibitor MI-2 significantly induced beta-cell replication.
Induction of Beta Cell Replication by Small Molecule-Mediated Menin Inhibition and Combined PKC Activation and TGF-beta Inhibition as Revealed by A Refined Primary Culture Screening. · Pahlavanneshan S, Behmanesh M, Tahamtani Y, Hajizadeh-Saffar E, Basiri M, Baharvand H · Cell Journal 2021What this evidence cannot show
Rat islets, methods-development paper, image-analysis proliferation readout, same group as E1 so not fully independent.
Evidence that argues against this (1)
- A replication signal in rodent islet monolayers is a weak predictor of human in-vivo beta-cell expansion; the field is littered with hits that did not translate. Pahlavanneshan S et al. 2020
Human-tissue counterpart of the mouse in-vivo phenotype: MI-2 plus TGF-beta inhibition replicates adult human beta cells without loss of insulin production
MI-2 blocks the menin-MLL interaction; the resulting human beta-cell replication runs through down-regulation of CDKN1A, CDKN1B and CDKN2C - the same restraint whose loss drives Men1 neuroendocrine tumours
- ← related toThe endocrine cell's resting state is an actively maintained G1 restraint, and menin is what maintains it
the pharmacological release of the same state