GenemoderateQ33-niche-protein-layer

LEPR - the marker that defines the SCF-supplying perivascular niche cell, the receptor for an adipocyte signal that blunts cytarabine, and a gene_exact query that returns the wrong protein first

also called OBR · leptin receptor · CD295 · DB

LEPR is the receptor for leptin, and the marrow cells that carry it are the ones that feed blood stem cells. In leukaemia, leptin acting through this receptor rewires blast metabolism so that cytarabine kills less well, and blocking the receptor restored chemosensitivity in mice.

The same thing, for a scientist

LEPR (UniProt P48357, 1,165 aa, a class I cytokine receptor) matters here twice over. As a MARKER it defines the perivascular stromal population whose *Scf* deletion depletes HSCs [E2] - LEPR+ cells are the principal niche-factor source in adult marrow. As a RECEPTOR it carries an adipocyte signal into the blast: elevated marrow leptin and blast LEPR associate with poor cytarabine clearance and reduced survival in newly diagnosed AML; exogenous leptin blunts cytarabine cytotoxicity in human AML lines, primary blasts and two syngeneic mouse models including MLL-AF9; the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukaemia growth; and mechanistically leptin drives JAK2/STAT3, raises complex I activity, OXPHOS and mitochondrial ROS, and the mtROS surge activates a compensatory antioxidant programme that shields blasts from drug-induced oxidative damage [E3]. The accession is a rule-62 trap: `gene_exact:LEPR` returns TWO reviewed human records and the 131-aa LEPROT comes back FIRST [E1].

What it looks like

LEPR1,165 aa

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

Go deeper

The accession trap, measured live

gene_exact:LEPR AND organism_id:9606 AND reviewed:true returns two reviewed human records, in this order:

order	accession	entry	primary gene	length
1	O15243	OBRG_HUMAN	LEPROT	131 aa
2	P48357	LEPR_HUMAN	LEPR	1,165 aa

LEPROT (leptin receptor overlapping transcript, OB-RGRP) is a different protein that merely carries LEPR among its synonyms. The wrong one is first, exactly the BACH1/TCF3/LEO1 shape rule 62 and the accession-resolution rule describe, and the length difference - 131 against 1,165 - is what catches it. An agent that took the first hit would attach a 131-residue protein's accession to every claim in this entry, and verify-accessions.py would pass it, because the failure is a synonym match rather than a typo. No row for LEPR or LEPROT existed in data/symbol-collisions.json when it was read at the start of this beat (2026-09-22, 177 rows).

Two different roles, and only one of them is about the blast

As a niche marker. Conditional deletion of Scf from Lepr-expressing perivascular stromal cells depletes HSCs, and deleting it from both endothelium and Lepr+ cells removes most of them 2. LEPR is therefore the label on the compartment that this graph elsewhere calls the perivascular/sinusoidal niche, and its importance in that role has nothing to do with leptin signalling into the leukaemia.

As a receptor on the blast. Marrow adipose tissue supplies leptin; blast LEPR reads it; and the consequence is metabolic rather than adhesive - JAK2/STAT3, complex I, OXPHOS, an mtROS surge and a compensatory antioxidant programme that blunts cytarabine 3. This is the third independent route by which this graph's niche layer arrives at redox as the chemoprotective mechanism: nestin+ BMSC glutathione, CXCL12-dependent redox balance in MLL::AF9, and now leptin-driven antioxidant compensation. mechanism-niche-chemoprotection-kmt2a already records the pattern; this entry supplies the receptor.

Facts and figures

gene symbol	LEPR
uniprot	P48357
length AA	1165
accession resolution	RULE-62 TRAP, MEASURED LIVE 2026-09-22. gene_exact:LEPR AND organism_id:9606 AND reviewed:true returns TWO reviewed human records and the WRONG ONE IS FIRST: O15243 / OBRG_HUMAN / primary gene LEPROT / 131 aa, then P48357 / LEPR_HUMAN / primary gene LEPR / 1,165 aa. LEPROT carries LEPR as a synonym, which is why the exact-looking query matches it. The primary gene name was read back from both records and the length checked (131 versus 1,165) before P48357 was selected. An automated pass taking the first hit would attach a 131-residue accession to this gene and pass verify-accessions.py, because the failure is a synonym match rather than a typo.
localization	CELL MEMBRANE and BASOLATERAL CELL MEMBRANE, both ECO:0000269 on UniProt P48357, with isoform E annotated Secreted by similarity (ECO:0000250) rather than experimentally. The secreted isoform is not a curiosity: a soluble leptin receptor buffers circulating leptin, so the ligand availability that E3's mechanism depends on is set by the ratio of membrane to soluble receptor, and no leukaemia study found in this beat measures it. The two intracellular regions at 893-898 and 898-906 are the JAK2- and STAT3-coupling elements that E3's mechanism runs through, so the domain map and the mechanism are the same object here.
subnuclear localization	NOT APPLICABLE BY TOPOLOGY FOR THE RECEPTOR, WITH THE PATHWAY'S NUCLEAR STEP IN A DIFFERENT PROTEIN. LEPR is a single-pass type I membrane receptor: 818 of 1,165 residues extracellular, no chromatin-binding module, no NLS on the record. The nuclear event in this axis belongs to STAT3, which LEPR phosphorylates via the 898-906 region and which then translocates - so the axis has a genuine nuclear arm and the receptor is not in it. This field does NOT claim nuclear LEPR was sought and excluded; no such search was run, and a curated feature table's silence is not evidence (see counter-evidence on E1).
subnuclear absence class	not-applicable-by-topology
cell type	TWO DIFFERENT CELLS, and the distinction is the point. (1) LEPR+ PERIVASCULAR STROMAL CELLS - the niche compartment whose Scf is required for HSC maintenance [E2]; here LEPR is a marker, and this graph holds concept-perivascular-sinusoidal-niche and cell-type-car-cell for the same population. (2) THE LEUKAEMIC BLAST - blast LEPR is the receptor through which marrow adipocyte leptin blunts cytarabine [E3]; this graph holds cell-type-bone-marrow-adipocyte as the ligand source. Reading the marker sense as the signalling sense is the commonest error available with this gene.
cell state	A CHEMORESISTANT, OXPHOS-HIGH, ANTIOXIDANT-BUFFERED BLAST STATE. Leptin through LEPR raises complex I activity, OXPHOS and mitochondrial ROS, and the mtROS surge switches on a compensatory antioxidant programme that shields the blast from cytarabine-induced oxidative damage; the LEPR antagonist Allo-aca reverses the chemoresistance without changing baseline growth [E3]. This is the same terminal state that nestin+ BMSC glutathione support and CXCL12-dependent redox balance produce by other routes - three independent inputs, one output.
epigenetic readout	NOT MEASURED AT THE LOCUS; THE PATHWAY'S CHROMATIN ARM IS STAT3, NOT A HISTONE-MODIFYING ENZYME. No histone-mark, DNA-methylation or menin-occupancy measurement at LEPR in a KMT2A-rearranged system was found. (LEPR[tiab] OR leptin[tiab]) intersected with the KMT2A/MLL half returns 2 records total - E3 and an extracellular-vesicle paper already held elsewhere in this graph - so there is very little literature for a chromatin measurement to be hiding in, and the bound is correspondingly informative. ABSENCE CLASS: never-measured. Bounded over titles and abstracts (rule 80).
shown for fusion	PARTIALLY, for murine MLL-AF9 only, and as one of two models rather than the headline system: exogenous leptin blunted cytarabine cytotoxicity in two syngeneic mouse models of which MLL-AF9 is one, and Allo-aca restored chemosensitivity [E3]. NO for KMT2A-rearranged B-ALL, NO for KMT2A::AFF1, NO for any infant sample, and NO for the marker sense - nobody has asked whether LEPR+ perivascular cells are the operative niche compartment in KMT2A-rearranged disease as opposed to normal haematopoiesis.
intact union membership	ABSENT from the 277-partner IntAct REST union of the six core baits (analyses/interactome-union-migrated-to-rest/results.json, generated 2026-09-22), checked on the symbol and on P48357.
collision note	NEW ROW CANDIDATE, MEASURED HERE. The registry was read first (2026-09-22, case-sensitive over d['collisions'], 177 rows) and contained no row for LEPR, LEPROT, SGPP1, P48357 or O15243. The trap is a rule-62 multiple-reviewed-record ordering failure: gene_exact:LEPR returns LEPROT (O15243, 131 aa) BEFORE LEPR (P48357, 1,165 aa) because LEPROT lists LEPR as a synonym. Discriminator: length, 131 versus 1,165. A second instance was measured in the same session and belongs with it - gene_exact:SPP1 also returns two reviewed records, P10451 (osteopontin, 314 aa) and Q9BX95 (SGPP1, 441 aa); there the correct record happens to be first, so the query is safe today and is not guaranteed to stay so.

domains

domains — the numbers behind the chart

[
  {
    "name": "Signal peptide",
    "start": 1,
    "end": 21
  },
  {
    "name": "Fibronectin type-III 1",
    "start": 239,
    "end": 333
  },
  {
    "name": "Ig-like domain",
    "start": 331,
    "end": 429
  },
  {
    "name": "Leptin-binding region",
    "start": 467,
    "end": 484
  },
  {
    "name": "Fibronectin type-III 2",
    "start": 539,
    "end": 634
  },
  {
    "name": "WSXWS motif",
    "start": 622,
    "end": 626
  },
  {
    "name": "Fibronectin type-III 3",
    "start": 639,
    "end": 732
  },
  {
    "name": "Fibronectin type-III 4",
    "start": 740,
    "end": 833
  },
  {
    "name": "Extracellular topological domain",
    "start": 22,
    "end": 839
  },
  {
    "name": "Transmembrane (helical)",
    "start": 840,
    "end": 862
  },
  {
    "name": "Cytoplasmic topological domain",
    "start": 863,
    "end": 1165
  },
  {
    "name": "Box 1 motif (JAK binding)",
    "start": 871,
    "end": 879
  },
  {
    "name": "Region required for JAK2 activation",
    "start": 893,
    "end": 898
  },
  {
    "name": "Region required for STAT3 phosphorylation",
    "start": 898,
    "end": 906
  }
]

depmap essentiality

{
  "depmap_common_essential": false,
  "tissue_blocks": 29,
  "n_screens": 1258,
  "mean_gene_effect": -0.0795,
  "min_gene_effect": -0.8229,
  "max_gene_effect": 0.9306,
  "n_lines_at_or_below_minus_1": 0,
  "open_targets_data_version": "year 26, month 06",
  "open_targets_api_version": "26.6.3",
  "fetched": "2026-09-22",
  "control": "Live zero-screen control in the same call and code path: MEN1 returned 29 tissue blocks, 1,258 screens, mean gene effect -0.3616, minimum -2.5262, 79 lines at or below -1.0 - so a zero count of dependent lines here is a measured zero, not an empty payload with a passing approvedSymbol readback. DepMap release recorded as Open Targets dataVersion year 26 month 06 (rule 83), API 26.6.3, fetched 2026-09-22. No median-split proportion is reported (rule 84). AND THE NULL IS AN ABSENCE BY CONSTRUCTION: DepMap screens cells in monoculture with no stroma, so a niche factor acting in trans cannot score however essential it is in vivo. The figure is recorded so nobody re-derives it and mistakes it for a finding."
}

How this could bite us back

LEPTIN SIGNALLING IS NOT OPTIONAL IN A CHILD. Loss-of-function LEPR mutation in humans causes severe early-onset obesity, hyperphagia and hypogonadotropic hypogonadism. A LEPR antagonist given to an infant is being given to a patient in whom this pathway is actively governing growth, appetite and the onset of puberty, and the AML cohort that motivates it is adult. Allo-aca's clean 'no effect on baseline growth' profile in mice says nothing about that.
THE PROTECTIVE DIRECTION MAY NOT GENERALISE. E3's mechanism is that mtROS triggers a compensatory antioxidant programme. In KMT2A-rearranged AML specifically, hypoxia induction SENSITISED cells to venetoclax plus a menin inhibitor rather than protecting them, so 'add oxidative stress, get protection' is not a rule in this disease and a LEPR-directed combination could be neutral or antagonistic depending on the partner drug.
THE SAME RECEPTOR MARKS THE SUPPORT CELL. LEPR+ perivascular stroma is the compartment whose SCF the patient's own HSCs need [E2]. A systemic LEPR-directed agent acts on the niche cell and the blast at once, and the two effects point in opposite directions for marrow recovery.
Allo-aca is a peptide antagonist with no paediatric exposure, no leukaemia trial and no published exposure-response in children; there is no clinical route to this mechanism today.

Still open

Is the leptin-LEPR chemoresistance circuit present in infant KMT2A::AFF1 B-ALL? Infant marrow has a markedly different adipocyte content from adult marrow, which makes the ligand availability - not the receptor - the variable that might differ most between the index disease and the AML cohorts of E3.
Does blocking LEPR blunt the OTHER redox-mediated protections in this graph (nestin+ glutathione, CXCL12-dependent redox balance), or are the three circuits additive?
Which perivascular marker names the cell that matters in leukaemia - LEPR or nestin? E2's conditional deletions separate them for normal HSC maintenance and nobody has repeated the comparison in a KMT2A-rearranged model.

Every source behind this entry (4)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The reviewed human leptin receptor is UniProt P48357 (LEPR_HUMAN), 1,165 aa, a single-pass type I membrane class-I cytokine receptor with four fibronectin type-III domains, an Ig-like domain, a leptin-binding region at 467-484, a WSXWS motif at 622-626 and Box 1 at 871-879; a gene_exact:LEPR query returns two reviewed human records and the 131-aa LEPROT (O15243) is returned first.
UniProtKB P48357 (LEPR_HUMAN) - Leptin receptor; and O15243 (OBRG_HUMAN) - LEPROT · UniProtKB 2026
What this evidence cannot show
Both records fetched live 2026-09-22 through gene_exact:LEPR AND organism_id:9606 AND reviewed:true, n=2, and the primary gene name was read back from each before selecting (rule 62). P48357's subcellular locations are Cell membrane and Basolateral cell membrane (ECO:0000269), with isoform E secreted (ECO:0000250, i.e. inferred by similarity and not experimental). The soluble receptor isoform is a real species and a circulating leptin buffer.
Evidence that argues against this (1)
- A curated feature table records what curators accepted, not what was sought and excluded, so no absence claim follows from it. The worked example is in this beat: UniProt P61073 annotates no nuclear localisation signal for CXCR4 while a mapped, mutated, functionally tested NLS at 146-RPRK-149 is published. Bao Y et al. 2019
E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In mouse, conditional Scf deletion from Lepr-expressing perivascular stromal cells depletes bone marrow HSCs, and deletion from both endothelial cells and Lepr-expressing perivascular cells removes most HSCs, establishing LEPR+ perivascular stroma as a required niche-factor source.
Endothelial and perivascular cells maintain haematopoietic stem cells · Ding L, Saunders TL, Enikolopov G, Morrison SJ · Nature 2012
PMID 22281595 DOI
What this evidence cannot show
Mouse, normal haematopoiesis, no leukaemia. This establishes LEPR as a MARKER of the required source compartment; it does not show that leptin signalling through LEPR is what those cells need, and conflating the marker with the pathway is the easiest error to make with this gene. Read from the abstract.
Evidence that argues against this (1)
- The same experiment found Scf deletion from nestin-cre and nestin-creER-expressing cells had NO effect on HSC frequency or function, so the LEPR+ and nestin+ perivascular labels do not mark functionally equivalent populations - and this graph holds cell-type-nestin-msc as an active leukaemia-supporting compartment on separate evidence. Which marker names the operative cell is unresolved. Ding L et al. 2012
E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Elevated bone-marrow leptin and blast LEPR associate with poor cytarabine clearance and reduced survival in newly diagnosed AML; exogenous leptin blunts cytarabine cytotoxicity in human AML lines, primary blasts and two syngeneic mouse models (MLL-AF9 and AML1-ETO9a); the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukaemia growth; and leptin upregulates LEPR and triggers JAK2/STAT3 signalling that raises mitochondrial complex I activity, oxidative phosphorylation and mitochondrial ROS, with the mtROS surge activating a compensatory antioxidant programme that shields blasts from drug-induced oxidative damage.
Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia · Liao X, Dai W, Xu X, et al. · Cell Death Dis 2026
PMID 41730833 DOI
What this evidence cannot show
AML throughout - the MLL-AF9 arm is one of two syngeneic mouse models and is myeloid, not infant B-lineage KMT2A::AFF1 (rule 73). The patient association is correlative and the abstract gives no cohort size, no multivariable adjustment and no effect size, so the clinical half is weaker than the mechanistic half. 'Without altering baseline leukaemia growth' is the claim that makes Allo-aca interesting and is also the claim most in need of the figures, which were not opened (rule 80). Read from the abstract.
Evidence that argues against this (1)
- The direction of the redox argument is contested within this graph's own niche layer. In KMT2A-rearranged AML, hypoxia induction SENSITISED cells to venetoclax plus MI-503 rather than protecting them, with the combination repressing HIF-1A and HDAC9 - so 'more oxidative stress protects the blast' is not a general rule in this disease and the leptin circuit's protective direction cannot be assumed to transfer to other stressors. Ling Q et al. 2023
E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
LEPR is not a cell-intrinsic dependency in DepMap: 29 tissue blocks, 1,258 screens, mean gene effect -0.0795, range -0.8229 to 0.9306, zero lines at or below a gene effect of -1.0.
Open Targets Platform GraphQL - target.depMapEssentiality for ENSG00000116678 (LEPR), with meta.dataVersion · Open Targets Platform / DepMap 2026
What this evidence cannot show
Live zero-screen control in the same call and code path: MEN1 returned 29 tissue blocks, 1,258 screens, mean gene effect -0.3616, minimum -2.5262, 79 lines at or below -1.0 - so a zero count of dependent lines here is a measured zero, not an empty payload with a passing approvedSymbol readback. DepMap release recorded as Open Targets dataVersion year 26 month 06 (rule 83), API 26.6.3, fetched 2026-09-22. No median-split proportion is reported (rule 84). AND THE NULL IS AN ABSENCE BY CONSTRUCTION: DepMap screens cells in monoculture with no stroma, so a niche factor acting in trans cannot score however essential it is in vivo. The figure is recorded so nobody re-derives it and mistakes it for a finding. LEPR is the sharpest case of the construction problem in this tranche, because E3's entire phenotype is conditional on exogenous leptin: a screen run without the ligand is measuring a receptor with nothing to receive, and the paper itself reports that antagonising LEPR does not alter BASELINE leukaemia growth - which is precisely what a DepMap screen measures.
Evidence that argues against this (1)
- The same monoculture assay returns an equally flat null for CXCR4 (mean +0.0399, zero lines at or below -1.0) while an in vivo syngeneic MLL-AF9 CRISPR screen made CXCR4 a TOP cell-surface dependency whose deletion eradicated leukaemia. That pair is a direct demonstration that a DepMap null for a niche gene is uninformative about in vivo requirement. Ramakrishnan R et al. 2020

Connected to

part of →The perivascular and sinusoidal niche — where the functional evidence actually sits, and where the marrow is genuinely hypoxic
LEPR+ perivascular stroma is the required SCF source compartment
← co-occurs withKITLG (stem cell factor) - the niche ligand of KIT, zero mentions anywhere in this graph, and its own symbol collides with the SCF ubiquitin ligase this corpus talks about constantly
Scf deletion from Lepr-expressing perivascular cells depletes HSCs - LEPR marks the KITLG source
← related toBone-marrow adipocyte — the fat cell that suppresses normal blood formation and feeds leukaemia a chemoresistance signal
marrow adipocyte leptin is the ligand read by blast LEPR
depends on →Niche-mediated chemoprotection in KMT2A-rearranged leukaemia — real for cytarabine, unsupported for menin inhibitors, and the one hypoxia experiment points the other way
leptin-LEPR JAK2/STAT3 raises OXPHOS and mtROS and blunts cytarabine in MLL-AF9
confers resistance to →Cytarabine - the one conventional drug KMT2A-rearranged infant ALL is MORE sensitive to, and the only case in this beat where a mechanism changed a protocol
leptin-LEPR signalling blunts cytarabine cytotoxicity; the LEPR antagonist Allo-aca restores it
← supportsNiche proteins enumerated and NOT written in this tranche, and four symbol traps measured while doing it - three of them new to the registry
measures the gene_exact:LEPR ordering trap recorded in that entry