Oncofusion

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Genestrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.

NR3C1 - the receptor the single most prognostic drug in this disease acts through, and the fusion suppresses it

also called glucocorticoid receptor · GR · GRL · P04150

Steroids are the backbone of treatment for this leukaemia, and how well a baby's blasts melt away in the first week of steroid treatment is one of the strongest predictors of whether they will survive. NR3C1 is the protein inside the cell that steroids actually grab hold of, so it is the doorway the whole effect passes through - and there is evidence that the fusion protein driving this leukaemia turns that doorway down.

The same thing, for a scientist

NR3C1 (P04150, 777 aa) encodes the glucocorticoid receptor, the obligate mediator of prednisolone and dexamethasone action. **Prednisone response is the fourth-ranked prognostic factor in Interfant-06** and defines the high-risk group, so NR3C1 sits underneath a stratifier rather than beside one. In this disease specifically, **NG2/CSPG4 is a direct MLL-AF4 target gene that suppresses NR3C1 and underlies glucocorticoid resistance** (PMID 39093982) - a route from the fusion to the receptor that does not require an NR3C1 lesion.

Go deeper
Why this gene sits under a stratifier

Glucocorticoids are not adjuncts here. Interfant-06 reports KMT2A rearrangement as the most important prognostic factor for event-free survival, followed by age, white cell count and prednisone response - and poor prednisone response is one of the criteria defining the high-risk group. NR3C1 is the receptor that response runs through.

The fusion reaches it without mutating it. PMID 39093982 identifies NG2/CSPG4 as a direct MLL-AF4 target gene that suppresses NR3C1 and thereby underlies glucocorticoid resistance in MLLr B-ALL. That matters for how resistance should be looked for: a sequencing panel searching for NR3C1 lesions would miss a transcriptional suppression mechanism entirely.

And the measurement everyone quotes is of a different molecule. Every in-vitro resistance figure in this disease - the >580-fold prednisolone resistance, the further >7.4-fold for t(4;11) - is prednisolone. Prednisone is a prodrug and is inert in culture, so no in-vitro prednisone measurement exists, while the clinical prognostic factor is prednisone response. See drug-prednisone and drug-prednisolone, which this graph deliberately carries as two entries.

Facts and figures
uniprotP04150
length AA777
gene primaryNR3C1
named in entries when written17
gene symbolNR3C1
gene symbol notepromoted from gene_primary 2026-09-20: verify-accessions.py reads data.gene_symbol, so a gene_primary-only entry was being length-checked or id-inferred rather than symbol-asserted
uniprot synonyms
[
  "GRL"
]
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.0347,
  "chronos_mean_other_leukaemia": -0.0067,
  "difference": -0.0279,
  "pan_essentiality_all_lines": -0.0075,
  "selectivity_rank": 5606,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}
How this could bite us back
  • Glucocorticoids are the backbone of this treatment and nothing here argues for reducing them. What this entry warns against is looking for glucocorticoid resistance by sequencing NR3C1: the documented route in this disease is transcriptional suppression by an MLL-AF4 target gene, which a mutation panel does not see.
  • Prednisone response is a stratifier that assigns infants to high-risk therapy. Any claim about improving it must specify prednisone or prednisolone, because the prognostic factor and every in-vitro measurement are different molecules.
Still open
  1. Does NR3C1 appear among the drug-response gene alterations in the relapse-genomics cohort? The abstract does not say and the full text was not read.
  2. How large is the NG2-mediated NR3C1 suppression, and is it sufficient to explain the clinical prednisone-response split?
  3. Which NR3C1 isoform operates in infant KMT2A-rearranged blasts?
Every source behind this entry (3)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    NG2/CSPG4 is a direct target gene of MLL-AF4 that underlies glucocorticoid resistance in MLL-rearranged B-cell acute lymphoblastic leukaemia by regulating NR3C1 expression.

    NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression · Lopez-Millan B, Rubio-Gayarre A, Vinyoles M, Trincado JL, Fraga MF, Fernandez-Fuentes N, Guerrero-Murillo M, Martinez A, Velasco-Hernandez T, Falgas A, Panisello C, Valcarcel G, Sardina JL, Lopez-Marti P, Javierre BM, Del Valle-Perez B, Garcia de Herreros A, Locatelli F, Pieters R, Bardini M, Cazzaniga G, Rodriguez-Manzaneque JC, Hanewald T, Marschalek R, Milne TA, Stam RW, Tejedor JR, Menendez P, Bueno C · Blood 2024
    PMID 39093982DOI
    What this evidence cannot show

    Abstract fetched and read back on an earlier cycle and re-checked here; full text not read. **Strong within the reported system, MLLr B-ALL.** The claim is that NG2 regulates NR3C1 expression, not that NR3C1 is mutated - which is the part that matters for how resistance is looked for. **The magnitude of the NR3C1 change and whether it is sufficient to explain the clinical resistance are not established here**, and the beat that first carried this paper recorded that four load-bearing findings in the immunophenotype layer come from one group with no independent replication.

    Evidence that argues against this (1)
    • Glucocorticoid resistance in this disease has at least four reported mechanisms - MCL-1, S100A8/A9-calcium, FYN/LCK-annexin A2-p11 and PI3K/FCGR1B - and a receptor-level route is only one of them. High MCL-1 tracks prednisolone resistance independently of NR3C1, so a therapy restoring receptor levels would not obviously restore sensitivity. Stam RW et al. 2010
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Whole-genome and exome sequencing of 36 infants and children with relapsed KMT2A-rearranged ALL or AML, with longitudinal deep sequencing of 257 samples from 30 patients, found somatic alterations in drug-response genes - most commonly TP53 and IKZF1, in 64% - highly enriched in early-relapse ALL.

    The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia · Ahlgren L, ..., (see record) · Nature Communications 2025
    PMID 41062506DOI
    What this evidence cannot show

    Abstract fetched and read back 2026-09-20; full text not read. Carried on this entry as the relapse-genomics context for drug-response genes in this disease. **NR3C1 is NOT named in the abstract**, so this entry does not claim that NR3C1 lesions were found - only that drug-response gene alterations are enriched at early relapse, which is the class NR3C1 would belong to if present. Resolving whether NR3C1 appears requires the full text.

    Evidence that argues against this (1)
    • Enrichment of drug-response gene alterations at relapse does not establish that they caused the relapse; a clone surviving therapy accumulates such lesions whether or not they drive the survival, and the design is not able to separate selection from passenger accumulation in a heavily pretreated population. Lopez-Millan B et al. 2024
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The reviewed human UniProt record for NR3C1 is P04150, 777 amino acids, primary gene name NR3C1, protein name glucocorticoid receptor, with GRL as its sole listed gene synonym.

    What this evidence cannot show

    Fetched from the UniProt REST API on 2026-09-20 with gene_primary and length read back, per brief rules 66/68/69. Established for the database state on that date. **NR3C1 has extensive well-documented isoform biology - GR-alpha and GR-beta among others - and a canonical length does not capture which isoform operates in a blast**, which is the same class of limit recorded for PKM2.

    Evidence that argues against this (1)
    • An accession and a length verify identity and say nothing about function; NR3C1 is among the genes where the canonical record is least informative, because receptor activity depends on isoform, phosphorylation state and chaperone availability rather than on sequence. Lopez-Millan B et al. 2024
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