Why this one rare leukaemia was thought to decide an argument about a drug used in a commoner one - and why it decides less than the title says (corrected 2026-09-21)

1. A KMT2A fusion is two things stuck together: an N-terminal piece of KMT2A that decides where on the genome to sit, and a partner that decides what to do when it gets there. The 'where' includes a grip on menin.
2. Menin inhibitors break that grip. Revumenib is approved on exactly that rationale.
3. CALM-AF10 has the 'what to do' and not the 'where'. It carries the same AF10 module, which grabs the same DOT1L enzyme through the same physical contact - but its other half is a clathrin adaptor with no grip on menin and no CpG-island targeting module.
4. Yet it produces the same output: HOXA5/7/9/10 and MEIS1 switched on, maturation blocked, and an absolute requirement for DOT1L.
5. So the question becomes sharp. Is menin needed because the HOXA programme needs it, or because a KMT2A fusion needs it? These have been treated as the same statement. They are not, and CALM-AF10 separates them.

Step 5 does not follow as cleanly as written, and this is the correction added 2026-09-21. The step assumes that menin dependence requires a menin-binding motif in the driving oncoprotein. Two counter-examples are published: NPM1-mutant AML has no fusion and responds to menin inhibition clinically, and NUP98-rearranged AML has no KMT2A and is menin-MLL1-dependent in vitro and in xenografts, through WILD-TYPE MLL1 rather than through a fusion-borne motif. Wild-type MLL1 is present in every cell. So the corrected form of step 5 is: is menin needed because a KMT2A FUSION needs it, or because the HOXA programme needs an MLL1 that menin holds on chromatin - whether that MLL1 is fused or not? CALM-AF10 still separates those two, but only in one direction, because a positive result is now the expected one.

Three things. The cells exist - U-937 is a standard laboratory line carrying this fusion, sold by every cell bank. The drug exists and is approved. And nobody has done it: as of 2026-09-20, joining any CALM-AF10 name to any menin name returns zero published records, with the operand controls run to prove the search works. The experiment is two weeks and the answer changes what this project believes either way.

There is a second instance, which makes the test stronger rather than merely repeating it: SET::NUP214, another T-ALL fusion with no KMT2A that also turns on HOXA and also works with DOT1L and CRM1. Run in the same plate, two unrelated lesions would answer the same question twice.

And the second instance is weaker than it looked. SET::NUP214 interacts with wild-type MLL via the SET acidic region of the fusion, and the two cooperatively enhance the HOXA10 promoter - so that lesion reaches HOXA through the very protein menin binds. Two KMT2A-free lesions that both route through MLL1 are one argument, not two, and the argument points toward menin involvement rather than away from it. Running both in the same plate is still the right design; describing it as answering the same question twice with unrelated lesions is not.

Nobody has run this. Everything above is a prediction from three indirect lines - the fusion's architecture, one cell line in a public dependency screen, and a chromatin screen performed in mouse MLL-AF9 cells. The graph's position is probably menin-independent, untested, and cheap to settle - not menin-independent.

Updated 2026-09-21: 'probably' is no longer defensible. Two published counter-examples show a leukaemia can be menin-dependent with no menin-binding motif of its own - NPM1-mutant AML, treated clinically on that basis, and NUP98-rearranged AML, where the dependency runs through wild-type MLL1. Chromatin-bound CRM1 recruits SET-Nup214 AND NPM1c to the HOX clusters, so the CRM1 address this graph treats as the KMT2A-free route is shared with a lesion that IS menin-dependent. And the revumenib protocol's HOX/MEIS cohort, which this entry already flagged as the sponsor betting the other way, now looks less like a bet and more like the reading of the evidence. The honest position is: untested, cheap to settle, and the prior has moved toward menin dependence rather than away from it.