Menin is dispensable for blood at rest and required for blood under stress - and that is a cell state, not a hedge
also called menin in regenerative haematopoiesis · the stress-revealed menin requirement
Mice without menin make normal blood while nothing is going wrong. Put those cells in competition or make them rebuild a blood system and they fail. So the safety argument for menin-blocking drugs depends on which state the patient's marrow is in, not on an average.
The same thing, for a scientist
After Men1 ablation, steady-state multilineage and myelo-erythroid progenitor numbers are preserved and blood counts are only modestly affected, while competitive transplantation exposes a marked functional defect in long-term HSCs despite normal initial homing; HoxA9 expression falls only modestly in menin-deficient HSCs, and the authors frame the requirement as one that is 'most apparent during situations of hematopoietic recovery' [E1]. Named here as a cell state rather than left as a caveat, because the whole therapeutic-index argument for menin inhibition is a statement about which state the marrow is in - and because a relapsed, heavily pretreated child's marrow is never in the state in which menin was shown to be dispensable.
The experiment, and what it does not show
Maillard et al. 1 ablated Men1 and found: modest effects on neutrophil, lymphocyte and platelet counts; preserved multilineage and myelo-erythroid progenitor numbers without stress; decreased B-lymphoid progenitors; and, on competitive transplantation, a marked functional defect in long-term HSCs with normal initial homing. HoxA9 fell only modestly.
What the paper does not show, and what this graph has occasionally read into it, is that menin loss is harmless. It shows that the readout which would detect harm - a blood count in an unstressed animal - is the wrong instrument.
The same phenotype shape appears for MLL1, and there it is contested
'Steady state preserved, competition fails' is exactly the shape McMahon et al. reported for conditional Mll deletion - and the paper published beside it reported fatal bone marrow failure within three weeks from a different allele (concept-two-founding-mll-conditional-knockouts-disagree-about-steady-state-blood).
The menin result rests on one allele in one laboratory. It has not been contradicted; it has also not been replicated with a second allele in this graph's reading. The confidence in 'menin inhibition should not cause myelosuppression as a class effect' should reflect that.
What state is a relapsed patient's marrow actually in?
Menin inhibitors are approved and trialled in relapsed or refractory disease - after intensive chemotherapy, often after transplant, in a marrow that is by definition regenerating. That is the state in which menin was shown to be required, not the state in which it was shown to be dispensable.
This does not predict a disaster; the clinical experience so far does not show one. It does mean the preclinical reassurance was generated in the wrong state, and that the relevant safety experiment - a menin inhibitor given across a transplant or a regeneration challenge, with LT-HSC competitive output as the endpoint - is the one nobody has published.
| state class | context-dependent requirement (steady state versus regeneration) |
|---|---|
| source | PMID 19228930 (mouse conditional Men1) |
| shown for fusion | NO - this is normal haematopoiesis in a fusion-free animal. The therapeutic-index argument imports it into a fusion context and that import has never been tested. |
| clinical relevance | menin inhibitors are used in relapsed or refractory disease, i.e. in regenerating marrow, which is the state in which menin is required rather than the state in which it is dispensable |
| what would test it | menin inhibitor dosed across a transplant or 5-FU regeneration challenge in mice, endpoint LT-HSC competitive output at 16 weeks - not blood counts |
requirement by state
{
"steady_state": "menin largely dispensable: multilineage and myelo-erythroid progenitor numbers preserved; counts modestly impaired; B-lymphoid progenitors decreased",
"competition_and_regeneration": "menin REQUIRED: marked functional defect in long-term HSCs on competitive transplantation, with normal initial homing"
}- Menin inhibition is given in the marrow state where menin is required. Impaired haematopoietic recovery would be attributed to prior chemotherapy or to the leukaemia itself, and no trial endpoint currently distinguishes the three.
- A safety package built on steady-state blood counts in unstressed animals cannot detect this liability by construction, and that is the package the class has.
- Does a pharmacological menin inhibitor reproduce the genetic stress phenotype? Genetic ablation and drug occupancy are not the same exposure, and this graph already holds concept-four-exposure-classes-of-menin-loss-are-not-interchangeable for exactly this reason.
- If HoxA9 barely moves in menin-deficient normal HSCs, what does the stress defect run through? The mechanistic account this graph uses for menin in blood is the HOXA axis, and in the normal stem cell that axis is not where the phenotype is.
- Is the B-lymphoid progenitor decrease relevant to a B-lineage leukaemia? Menin loss decreases B-lymphoid progenitors in normal mice, and the index fusion is a B-lineage disease. Nobody has asked whether that is a therapeutic bonus or a confound in interpreting response.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
After Men1 ablation, menin loss modestly impaired blood neutrophil, lymphocyte and platelet counts; without haematopoietic stress multilineage and myelo-erythroid bone marrow progenitor numbers were preserved while B lymphoid progenitors were decreased; competitive transplantation revealed a marked functional defect of long-term haematopoietic stem cells despite normal initial homing of progenitors; HoxA9 expression was only modestly decreased in menin-deficient HSCs; and the authors conclude menin regulates pathways essential during the adaptive HSC response to stress.
Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. · Maillard I, Chen YX, Friedman A, Yang Y, Tubbs AT, Shestova O, Pear WS, Hua X · Blood 2009What this evidence cannot show
Mouse, single conditional Men1 allele, one laboratory; abstract read, full text not opened. This PMID is already cited in six entries of this corpus including gene-men1 E3; this entry adds the STATE framing and the comparison to the contested Mll pair, not a new source. The modest HoxA9 fall is worth noting on its own: the graph's mechanistic story for menin in blood runs through HOXA9, and in normal HSCs removing menin barely moves it.
Evidence that argues against this (1)
- The same phenotype shape for the partner protein is contested: a second conditional Mll allele gave fatal bone marrow failure within three weeks where the first gave grossly normal steady-state blood. One allele is not a class statement. Jude CD et al. 2007
the menin therapeutic-index argument has the same phenotype shape and inherits the same uncertainty
menin is required for long-term HSC function under competition and recovery, not at steady state (PMID 19228930)
the compartment the defect is measured in
- related to →The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
the self-renewal state the defect is read out as