ESR1 / estrogen receptor alpha - menin's best-documented non-leukaemic partner, and the only one a menin inhibitor is being given to patients to disrupt on purpose

{
  "chronos_mean_kmt2a_rearranged": -0.0373,
  "chronos_mean_other_leukaemia": -0.0296,
  "difference": -0.0077,
  "pan_essentiality_all_lines": -0.0529,
  "selectivity_rank": 8143,
  "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."
}

{
  "subcellular": "THREE compartments, and which one dominates depends on the isoform. UniProt P03372 isoform 1: Nucleus (ECO:0000269 PubMed:12682286, 20074560), Cytoplasm (12682286, 24498420) and Cell membrane as a PERIPHERAL membrane protein (12682286), with a note that a minor fraction sits on the inner membrane. Isoform 3 (ER46) adds a palmitoylation-dependent plasma-membrane pool and a Golgi pool where ZDHHC7/ZDHHC21 palmitoylation occurs. The membrane pool is not an artefact - it has a named function in endothelial cells.",
  "subnuclear": "NOT ESTABLISHED IN ANY HAEMATOPOIETIC CELL, and not securely established anywhere. Ligand-induced nuclear foci and condensate behaviour are reported for ERalpha, but every such report read here is breast, endometrial or endothelial. Recorded as a TISSUE-BOUNDED absence rather than a gap: the measurement exists, in the wrong tissue.",
  "how_shown": "subcellular fractionation and immunostaining in human endothelial cells for the membrane pool (PMID 12682286); antibody immunofluorescence in HPA",
  "tissue_of_evidence": "BREAST, ENDOMETRIUM, CERVIX, FALLOPIAN TUBE and vascular endothelium. HPA RNA tissue-enhanced values: endometrium 103.7, cervix 80.7, fallopian tube 61.1 nTPM. This entry entered the graph through a menin/ER breast-cancer route and its localisation literature is entirely non-haematopoietic; nothing here may be quoted as leukaemia biology.",
  "hpa_call_is_suspect_and_is_recorded_as_such": "HPA v25.1 gives ESR1 main subcellular location VESICLES with Nucleoplasm only as an additional location, reliability Approved (not Supported or Enhanced). For a ligand-activated nuclear receptor whose canonical address is the nucleus, a vesicular main call in cell lines that are not oestrogen-receptor-positive is more likely an antibody or an expression-floor artefact than a finding. It is recorded here because suppressing a disagreeing measurement is worse than explaining it, NOT because it is believed.",
  "node": "localization-partner-baseline-compartment-is-often-miscalled"
}

{
  "haematopoietic_answer": "HAEMATOPOIETIC STEM CELLS, and essentially nothing below them. Oestrogen acting through ERalpha increases haematopoietic stem-cell self-renewal in female mice and during pregnancy (PMID 24451543) - a real and important haematopoietic ERalpha result. Against that, HPA Blood Atlas records ESR1 as Not detected in immune cells, distribution Not detected. The reconciliation is that the HSC result is a stem-and-progenitor compartment effect in mouse bone marrow, and HPA profiles mature human peripheral-blood immune cells.",
  "grade": "Class 1 expression plus one class-2 genetic result, in mouse, in normal haematopoiesis. No leukaemic ESR1 cell-type experiment.",
  "tissue_label_required": "Brief rule 73 applies in its strongest form for this entry. Every other ESR1 statement in this graph - the menin-ERalpha interaction, the H3K4me3 link, the KAT6A/menin combination - is BREAST. Write the tissue into the claim, not only the caveat."
}

{
  "state": "OESTROGEN-EXPOSED / PREGNANT. The one haematopoietic ERalpha state is hormonal: HSC self-renewal rises in females and further during pregnancy (PMID 24451543). This is a physiological state, not a leukaemic one.",
  "consequence_for_this_graph": "A menin inhibitor given to a child disrupts menin-ERalpha as well as menin-KMT2A. If ERalpha signalling supports normal HSC self-renewal, the on-target off-tumour cost of menin inhibition may include the stem compartment, and it would be sex-dependent. Nobody has measured this."
}

{
  "date": "2026-09-21",
  "tool": "NCBI E-utilities esearch, db=pubmed",
  "shape": "gene clause AND localisation clause AND KMT2A/MLL-fusion clause, one [tiab] tag per term (brief rule 94), every cytogenetic term quoted (brief rule 95)",
  "querytranslation_fusion_clause": "\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"KMT2A-rearranged\"[Title/Abstract] OR \"MLL-rearranged\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 9 11\"[Title/Abstract] OR \"MLL fusion\"[Title/Abstract]",
  "count": 2,
  "controls": {
    "fusion_clause_alone": 8743,
    "gene_clause_alone": 26844
  },
  "reading": "Counted in TITLES AND ABSTRACTS only; supporting figures were not searched (brief rule 80).",
  "title_check": "2 records, 0 of them a localisation experiment in a KMT2A-rearranged cell; one breast, one prostate."
}