LAMP5-directed therapy for KMT2A-rearranged leukaemia would meet the basal ganglia, in a disease treated in infants and routinely treated into the CNS
also called LAMP5 CNS risk
LAMP5 is one of the most brain-concentrated proteins in the body, at its highest in a deep brain region that is still developing in babies. Leukaemia therapy in this disease is deliberately directed into the nervous system, so a LAMP5-targeting treatment would go where the protein is.
The same thing, for a scientist
LAMP5 is the antigen the published MLL-rearranged surfaceome screen produced and a direct MLL-fusion target whose depletion blocks leukaemia growth [E1]. Its normal distribution is brain-dominated in two independent atlases: **HPA 297.8 nTPM in basal ganglia; GTEx 323.89 TPM in nucleus accumbens, 134.31 caudate, 85.09 putamen**, against a whole-body median of **1.21 TPM** [E2, E3]. Its 51-tissue profile does not track PTPRC (r = -0.30), so the signal is neural parenchyma. Three features compound the concern specifically for this disease: 1. **The patients are infants**, and the basal ganglia are developing. 2. **CNS-directed therapy is routine** in KMT2A-rearranged infant ALL, and CD19 CAR-T is known to act against CNS leukaemia - so the blood-brain barrier is not a protection that can be relied on. 3. **The gene is named for it** - BAD-LAMP, brain and dendritic cell-associated LAMP - so this is not an obscure secondary site. **The load-bearing uncertainty is surface presentation.** UniProt annotates LAMP5 at the cell membrane alongside endosome, ERGIC, cytoplasmic-vesicle, synaptic-vesicle and recycling-endosome membranes, and notes it recycles to the plasma membrane [E4]. If LAMP5 is predominantly intravesicular in neurons at steady state, the risk is notional; if it cycles to the neuronal surface, it is not. **Nobody has measured it.**
Why the whole-body median cuts the other way
GTEx puts LAMP5 at a whole-body median of 1.21 TPM - quieter outside the brain than almost any antigen in this beat's screen, and quieter than CD19's peripheral profile 3. For a modality that genuinely cannot reach the CNS, LAMP5 could have an exceptional therapeutic index.
So this is not a target to discard. It is a target whose entire risk profile collapses onto one binary question - is LAMP5 on the neuronal surface - and that question is answerable with immunohistochemistry on non-permeabilised paediatric brain tissue. A target whose risk reduces to one measurable binary is a good target to work on, which is the opposite of the conclusion a reader might draw from the headline number.
| kind | toxicity |
|---|---|
| severity | unknown - conditional entirely on neuronal surface presentation |
| mechanism | on-target/off-tumour engagement of LAMP5 on neurons, principally basal ganglia, in a CNS compartment that anti-leukaemia therapy is deliberately directed into |
| decisive measurement | Immunohistochemistry or flow on non-permeabilised paediatric neural tissue: is LAMP5 on the neuronal surface, or in vesicles? The entire risk collapses onto this binary. |
| mitigation | Establish neuronal surface presentation before any CNS-penetrant construct; consider a modality with deliberately poor CNS penetration, accepting that CNS disease then goes untreated by this agent; note that LAMP5's whole-body median of 1.21 TPM is otherwise exceptionally favourable. |
affects
[ "gene-lamp5" ]
normal expression — the numbers behind the chart
{
"HPA basal ganglia nTPM": 297.8,
"GTEx nucleus accumbens TPM": 323.89,
"GTEx whole-body median TPM": 1.21,
"r vs PTPRC": -0.298
}- This entry raises a toxicity objection to another group's target from mRNA alone and from an abstract. It is stated as conditional for that reason, and quoting it as 'LAMP5 is unsafe' would misrepresent it.
- If LAMP5 turns out to be intravesicular in neurons, it becomes one of the cleanest antigens in this entire screen - whole-body median 1.21 TPM - and this risk entry will have delayed a good target.
- Sparing the CNS to protect the basal ganglia means not treating CNS leukaemia, which is a leading site of relapse in this disease. The mitigation and the indication are in tension and no combination resolves it.
- Is LAMP5 surface-exposed on human neurons? Everything here waits on that one measurement.
- Does the proposing paper address brain expression in its body text? This entry rests on an abstract-level read and should be revised by anyone who reads the full paper.
- Would a LAMP5-directed agent that cannot cross the blood-brain barrier still be useful in a disease with frequent CNS involvement, or are efficacy and safety in direct conflict here?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
LAMP5 was identified as a predicted cell-surface protein overexpressed in MLL-rearranged leukaemia, is a direct target of the oncogenic MLL fusion protein, its depletion inhibits leukaemia growth in vitro and in vivo, and it was proposed as a novel immunotherapy target.
LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia. · Haematologica 2022What this evidence cannot show
Abstract read in full; figures and any normal-tissue discussion in the body were not read on this beat, so this entry cannot claim the authors ignored the issue - only that the abstract's stated method does not include a normal-tissue filter.
Evidence that argues against this (1)
- The authors may have addressed brain expression in the discussion or supplement. A risk entry built on an abstract-level read of somebody else's paper should be treated as provisional. Haematologica 2022
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
HPA consensus normal tissue puts LAMP5 at 297.8 nTPM in basal ganglia, against 2.1 in bone marrow and 5.3 in lymph node.
Human Protein Atlas, consensus tissue RNA nTPM across 51 normal tissues (rna_tissue_consensus.tsv); HPA release v25.1, fetched 2026-09-23 · Human Protein Atlas 2026What this evidence cannot show
Adult bulk brain mRNA; infant basal ganglia are not represented in either atlas.
Evidence that argues against this (1)
- Bulk tissue mRNA cannot distinguish an intravesicular protein from a surface-displayed one, and only the latter is a CAR target. UniProt 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
GTEx v8 puts LAMP5 at 323.89 TPM in nucleus accumbens, 134.31 in caudate and 85.09 in putamen, with a whole-body median of 1.21 TPM across 54 tissues.
What this evidence cannot show
Adult post-mortem tissue.
Evidence that argues against this (1)
- A 1.21 TPM whole-body median is exceptionally clean and is an argument FOR LAMP5 as a target, provided the CNS can be spared. Human Protein Atlas 2026
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q9UJQ1 annotates LAMP5 at Cell membrane together with endosome, ERGIC, cytoplasmic-vesicle, synaptic-vesicle, growth-cone and recycling-endosome membranes, with an extracellular topological domain at residues 30-235, and records recycling from the endocytic recycling compartment to the plasma membrane.
What this evidence cannot show
The topological domain is ECO:0000255 sequence-analysis inference; several location comments are ECO:0000250 by-similarity from mouse.
Evidence that argues against this (1)
- Multiple annotated compartments say nothing about steady-state distribution, which is the quantity that matters and which no database records. UniProt 2026
- related to →LAMP5 (BAD-LAMP) - a direct MLL-fusion target gene, a proposed immunotherapy antigen, and a brain protein
the CNS exposure that the normal-tissue axis reveals
infant basal ganglia are developing and CNS-directed therapy is routine in this disease