The innate-immune-rewired state — LAMP-5 is a direct fusion target that routes signalling away from interferon and toward NF-kB, and the cell depends on that routing
also called inflammatory signalling state · NF-kB-biased innate signalling · LAMP5-high state · TLR/IL-1R endosomal routing state
Leukaemia cells receive alarm signals through the same machinery as normal immune cells, but a protein called LAMP-5 — switched on directly by the fusion — diverts those signals down an inflammatory route and away from an antiviral one. Removing LAMP-5 flips the switch back and the cells stop growing.
The same thing, for a scientist
This is the closest thing the literature has to a baseline inflammatory-state characterisation in KMT2A-rearranged leukaemia, and it is a mechanism rather than a signature. Filtering large leukaemia expression repositories through the in silico human surfaceome for lineage-independent MLL-rearranged overexpression identified **LAMP5**, which is expressed highly and specifically in MLL-rearranged leukaemia and is a **direct target of the oncogenic MLL fusion protein**. LAMP5 depletion significantly inhibited leukaemia cell growth in vitro and in vivo. Functionally, LAMP-5 is a modulator of innate-immune pathways: **its downregulation inhibited NF-kB signalling and increased activation of type-1 interferon signalling downstream of Toll-like receptor and interleukin-1 receptor activation**, because LAMP-5 transfers signal flux from interferon-signalling endosomes to pro-inflammatory signalling endosomes; depletion of IRF7 partially rescued the growth inhibition. LAMP-5 is detectable on the surface and an antibody-drug conjugate against it specifically reduced viability in MLL-rearranged cells [E1]. Two things make this a state entry rather than a target entry. First, the cell is described as actively **holding an interferon response down** — that is a state, and it is the baseline the induced interferon state of `cell-state-interferon-herv-mhc2` acts against. Second, the dependence is on the routing, not on the receptor: IRF7 rescue shows the growth inhibition runs through the interferon arm being released.
The direction of the switch, which is the part to get right
LAMP-5 present → flux routed to pro-inflammatory (NF-kB) endosomes → NF-kB signalling on, type-1 interferon signalling held down → cell grows.
LAMP-5 depleted → NF-kB signalling inhibited, type-1 interferon signalling increased downstream of TLR/IL-1R → growth inhibited, and IRF7 depletion partially rescues 1.
The IRF7 rescue is the load-bearing experiment. Without it, LAMP-5 depletion inhibiting growth would be uninformative about mechanism; with it, the growth inhibition is shown to depend on the interferon arm that LAMP-5 was suppressing. So the cell is not merely inflamed — it is specifically avoiding an interferon response it would otherwise mount, and that avoidance is required.
What this predicts, and where it meets the menin-inhibitor result
cell-state-interferon-herv-mhc2 records that menin inhibition drives endogenous retrovirus expression, interferon-stimulated gene upregulation and MHC class II induction in KMT2A-rearranged AML. This entry records that the same disease maintains a direct-fusion-target protein whose job is to suppress interferon signalling.
Put together they make a testable prediction that neither paper states: a menin inhibitor should be more effective, or its interferon arm more pronounced, where LAMP-5 is low or depleted — and conversely, LAMP-5 expression is a candidate brake on the viral-mimicry mechanism the menin inhibitor depends on for its immunological effect. Nothing in either paper tests this and LAMP5 levels are not reported in the menin-inhibitor study.
It also makes LAMP5 a candidate resistance gene of an unusual kind: not a target mutation, not a bypass pathway, but an antigen-presentation brake that would blunt the immunological half of the drug's effect while leaving the transcriptional half intact.
A second, drug-induced route into the same axis
IMPDH inhibition — the mechanism of mycophenolate, a widely used immunosuppressant — kills MLL-fusion AML in vitro and, on alternate-day dosing, suppresses MLL-AF9-driven AML in vivo without devastating immune function; mechanistically it overactivates TLR-TRAF6-NF-kB signalling and upregulates VCAM1, and combining an IMPDH inhibitor with a TLR1/2 agonist was effective 2.
That is the same innate-immune axis moved in the opposite direction — more NF-kB, not less — and also killing the cells. Both cannot be a simple 'NF-kB is required' or 'NF-kB is lethal' story. The reconciliation the two papers jointly suggest is that this axis is tuned: the leukaemic cell needs a particular setting of the TLR/IL-1R output, and pushing it far in either direction is deleterious. That is a different and more useful claim than either paper makes alone, and it predicts that the combination of a LAMP-5-directed and an NF-kB-activating agent could be antagonistic.
| state definition | A configuration of innate-immune signal routing in which Toll-like receptor and IL-1 receptor input is directed preferentially to NF-kB-driven pro-inflammatory endosomes rather than to interferon-signalling endosomes, maintained by LAMP-5 and required for growth |
|---|---|
| fusion relationship | LAMP5 reported as a direct target of the oncogenic MLL fusion protein, expressed highly and specifically in MLL-rearranged leukaemia and described as lineage-independent |
| therapeutic handle | LAMP-5 is surface-detectable and an anti-LAMP-5 antibody-drug conjugate reduced viability specifically in MLL-rearranged leukaemias |
| opposing result | IMPDH inhibition overactivates TLR-TRAF6-NF-kB and also inhibits MLL-fusion leukaemia, so the axis appears tuned rather than monotonic (PMID 36453131) |
| untested prediction | LAMP5 level should modify the interferon and MHC-II induction produced by menin inhibition; LAMP5 is not reported in the menin-inhibitor immunology study and the menin axis is not reported in the LAMP-5 study |
switch direction
{
"lamp5_present": "flux to pro-inflammatory endosomes; NF-kB active; type-1 interferon suppressed; growth maintained",
"lamp5_depleted": "NF-kB inhibited; type-1 interferon increased downstream of TLR/IL-1R; growth inhibited; partially rescued by IRF7 depletion"
}atlas refs
[
{
"label": "LAMP-5 routes TLR/IL-1R flux away from interferon endosomes in MLL-r leukaemia",
"pmid": "33910331",
"title": "LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.",
"authors": "Gracia-Maldonado G, Clark J, Burwinkel M, et al.",
"venue": "Haematologica",
"year": 2022,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
},
{
"label": "IMPDH inhibition activates TLR-TRAF6-NF-kB and VCAM1 and suppresses MLL-fusion AML",
"pmid": "36453131",
"title": "IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.",
"authors": "Liu X, Sato N, Yabushita T, et al.",
"venue": "EMBO Mol Med",
"year": 2023,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}
]- An anti-LAMP-5 antibody-drug conjugate inherits the failure mode this graph already records for CD19-directed therapy: single-antigen pressure on a disease with documented lineage plasticity, and LAMP5 is reported as lineage-independent precisely because the cell can occupy either lineage.
- If the leukaemic cell depends on holding interferon signalling down, and a menin inhibitor works partly by turning interferon signalling up, then a LAMP-5-directed agent and a menin inhibitor may be redundant rather than additive, and nobody has tested the pair.
- IMPDH inhibitors are immunosuppressants. Using one as an antileukaemic agent in an infant who is already profoundly immunosuppressed by induction chemotherapy sets the antileukaemic mechanism against the infection risk, and the mouse reassurance about immune function was on an alternate-day schedule in a healthy immune system.
- LAMP5 is expressed in normal brain tissue as a neuronal protein; an antibody-drug conjugate's exclusion of that compartment depends on blood-brain barrier integrity, which in a leukaemia with documented CNS involvement and intrathecal therapy is not intact.
- Does LAMP5 expression modify the interferon and MHC class II induction produced by menin inhibition? If it does, LAMP5 is a resistance biomarker for the immunological half of that drug's effect, and it is measurable on the surface of the same cells.
- Why do two published interventions that move NF-kB in opposite directions both inhibit MLL-fusion leukaemia? Until that is resolved, no NF-kB-directed strategy in this disease is grounded.
- Is LAMP-5 really a direct fusion target, or a target of wild-type KMT2A detected by an N-terminal antibody that cannot tell them apart? This graph's attribution audit makes that the default question for any 'direct fusion target' claim, and the size-discriminating or junction-specific experiment has not been done for LAMP5.
- Is LAMP5 expressed in KMT2A-rearranged infant ALL specifically, at a level and surface density that would support an antibody-drug conjugate in an infant? 'Lineage-independent' is asserted from repository filtering rather than from matched primary infant cohorts.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Filtering large leukaemia expression repositories through the in silico human surfaceome to compile a lineage-independent MLL-rearranged gene signature identified LAMP5 as highly and specifically expressed in MLL-rearranged leukaemia and as a direct target of the oncogenic MLL fusion protein; LAMP5 depletion significantly inhibited leukaemia cell growth in vitro and in vivo; LAMP-5 is a modulator of innate-immune pathways whose downregulation inhibited NF-kB signalling and increased activation of type-1 interferon signalling downstream of Toll-like receptor and interleukin-1 receptor activation, attributable to LAMP-5 transferring signal flux from interferon-signalling endosomes to pro-inflammatory signalling endosomes; depletion of IRF7 partially rescued the growth inhibition caused by LAMP5 downregulation; and LAMP-5 was readily detected on the surface of MLL-rearranged cells, with an anti-LAMP-5 antibody-drug conjugate significantly decreasing viability specifically in MLL-rearranged leukaemias.
LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia · Gracia-Maldonado G, Clark J, Burwinkel M, Greenslade B, Wunderlich M, Salomonis N, et al., Lee LH · Haematologica 2022What this evidence cannot show
The signature was derived by in silico filtering of public repositories, so the specificity claim inherits whatever composition bias those repositories carry; 'lineage-independent' is asserted from that analysis rather than from matched lymphoid and myeloid primary cohorts. 'Direct target of the MLL fusion' rests on occupancy at the locus, and occupancy in this literature is almost always measured with N-terminal MLL antibodies that do not distinguish fusion from wild-type protein - the attribution problem this project has audited. The IRF7 rescue is partial, so the interferon arm is one contributor to the growth effect rather than the whole of it. Antibody-drug conjugate data are preclinical viability assays. Read: abstract only.
Evidence that argues against this (1)
- A required suppression of interferon signalling sits awkwardly beside the finding that a menin inhibitor's benefit in this disease runs partly THROUGH interferon: menin inhibition increases human endogenous retrovirus expression, consecutive interferon-stimulated gene upregulation and MHC class II, enhancing T-cell-mediated elimination. If the cell depends on holding interferon down, either the menin inhibitor overrides LAMP-5-mediated suppression - in which case LAMP5 level should modify the drug's immunological effect, which nobody has measured - or the two studies are describing different branches of interferon signalling that do not interact. Neither paper cites the other's axis. Read: abstract only. Fetsch V et al. 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Acute myeloid leukaemias with MLL fusions are susceptible to inosine monophosphate dehydrogenase inhibitors in vitro, and alternate-day administration of an IMPDH inhibitor suppressed the development of MLL-AF9-driven AML in vivo without devastating immune function; mechanistically IMPDH inhibition induced overactivation of Toll-like receptor-TRAF6-NF-kB signalling and upregulation of the adhesion molecule VCAM1, which contribute to the antileukaemia effect, and combined treatment with an IMPDH inhibitor and a TLR1/2 agonist effectively inhibited the development of MLL-fusion AML.
IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia · Liu X, ..., Goyama S · EMBO Mol Med 2023What this evidence cannot show
Myeloid only, and the in vivo model is MLL-AF9, so nothing is established for KMT2A::AFF1 or for lymphoid disease. IMPDH inhibitors are clinically used as immunosuppressants, and 'without having a devastating effect on immune function' is a qualitative statement about an alternate-day schedule in mice that would need careful re-derivation in an immunocompromised child. The mechanism is nucleotide-pool depletion with downstream innate signalling effects, so the TLR-NF-kB arm is a consequence of a metabolic perturbation rather than a direct innate-immune intervention. Read: abstract only.
Evidence that argues against this (1)
- The two innate-immune results in this disease move NF-kB in opposite directions and both report antileukaemic effect: LAMP5 depletion INHIBITS NF-kB and inhibits growth, while IMPDH inhibition OVERACTIVATES TLR-TRAF6-NF-kB and inhibits growth. Taken at face value they cannot both support a simple dependence of the leukaemic cell on NF-kB activity, so at least one of the growth effects is mediated by something other than the NF-kB change reported alongside it. This is unresolved, and it means neither result licenses an NF-kB-directed therapeutic strategy in this disease without first establishing which direction is deleterious. Read: abstract only. Gracia-Maldonado G et al. 2022
the baseline the induced state acts against: LAMP-5 actively routes TLR/IL-1R flux away from interferon signalling, and LAMP5 level is an untested modifier of the menin inhibitor's immunological effect
LAMP5 reported as a direct target of the oncogenic MLL fusion, expressed highly and specifically in MLL-rearranged leukaemia across lineages
IMPDH inhibition overactivates TLR-TRAF6-NF-kB and VCAM1 and suppresses MLL-AF9-driven AML — the same axis moved the opposite way, also antileukaemic
LAMP-5 routes TLR/IL-1R signalling toward NF-kB in MLL-rearranged cells; already in the graph, linked not duplicated
the corpus entry that already held the surfaceome screen, filed under innate immunity where no antigen beat could reach it
LAMP-5 routes innate-immune signalling from type-I interferon toward NF-kB; the cell state this graph already held