RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin

{
  "menin_region_paper": "aa 305-381 essential (PMID 11526476 abstract)",
  "menin_region_intact": "aa 300-376 necessary binding region (IntAct curation of the same paper)",
  "rela_region": "N-terminus sufficient",
  "method": "GST pull-down, western blot",
  "consequence": "menin represses p65-mediated transactivation, dose-dependently and specifically",
  "cofactor": "SIRT1 (deacetylates p65 K310)",
  "antagonist": "RPA2 (dissolves the menin-p65 complex)",
  "n_source_publications_in_intact": 1
}

{
  "finding": "RELA occupies promoters of crucial MLL target genes and sustains the MLL-dependent LSC programme; IKK/NF-kB required for wild-type and fusion MLL retention on chromatin",
  "source_pmid": "24054986",
  "models": "mouse MLL-AF1p, MLL-AF10, MLL-AF9; human AML methylation and expression cohorts",
  "menin_mentions_in_that_paper": 2,
  "menin_mentions_outside_reference_list": 0
}

{
  "kmt2a_records_raw": 16,
  "kmt2a_records_substantive": 3,
  "substantive_pmids": [
    "24054986",
    "36503469",
    "29320732"
  ],
  "aliases_searched": [
    "RELA",
    "p65",
    "NFKB3"
  ],
  "kmt2a_query": "(RELA[tiab] OR p65[tiab] OR NFKB3[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"mixed-lineage leukemia\"[tiab])",
  "alias_precision_note": "p65 is a word-like alias that labels several unrelated proteins and gel bands; every one of the 16 hits was title-checked and 13 were removed"
}

{
  "subcellular": "Cytoplasm and nucleus, with the partition under active control in BOTH directions. Import on stimulation is the textbook half; the half that matters for this graph is EXPORT - efficient nuclear export of p65-IkappaB-alpha complexes requires 14-3-3 proteins, and pharmacological XPO1 inhibition (eltanexor) causes nuclear accumulation of the IkappaB-alpha/NF-kappaB p65 complex. UniProt Q04206 (TF65_HUMAN, Transcription factor p65, 551 aa) was read back only to confirm the identifier; no localisation string was taken from it.",
  "subnuclear": "chromatin, at defined promoters - a genomic address in the right disease family. In MLL-fusion leukaemia the NF-kappaB subunit RELA occupies the promoter regions of crucial MLL target genes and sustains the MLL-dependent leukaemia stem cell program, and IKK/NF-kappaB signalling is required for retention of both wild-type and fusion MLL protein at those promoters. NO nuclear-body, speckle, nucleolar or heterochromatin assignment for RELA was found in any source read for this beat: (RELA OR \"NF-kappaB p65\")[tiab] AND (\"PML nuclear bodies\" OR speckle* OR \"nuclear bodies\")[tiab] returns 20 records and every one title-checked is either herbal/inflammation pharmacology or about a DIFFERENT protein's body localisation (IKK-epsilon, Tax, PML-RARA).",
  "how_shown": "chromatin immunoprecipitation of RELA at MLL target promoters with NF-kappaB suppression in MLL-fusion leukaemia (PMID 24054986); 14-3-3 dependence of p65-IkappaB-alpha export (PMID 27307493); XPO1 inhibitor-driven nuclear accumulation of the IkappaB-alpha/p65 complex (PMID 36110547)",
  "systems": "MLL-fusion leukaemia models for the chromatin work; non-haematopoietic cell lines and osteoclasts for the transport work",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a"
}

{
  "query": "(RELA[tiab] OR \"NF-kappaB p65\"[tiab]) AND (KMT2A[tiab] OR MLL[tiab])",
  "records": 9,
  "records_with_rela_localization": 0,
  "operand_controls": {
    "(RELA OR \"p65\" OR \"NF-kappaB p65\")[tiab] AND (\"PML nuclear bodies\" OR speckle* OR \"nuclear bodies\")[tiab]": 20
  },
  "date": "2026-09-21",
  "tool": "PubMed E-utilities esearch",
  "bound": "zero in titles and abstracts; supporting figures not searched. Rule 64 note: the complex form was run - 'IKK/NF-kB' is how PMID 24054986 frames itself and is why a bare CHUK/IKBKB subunit query misses it."
}

[
  "RELA",
  "p65",
  "NF-kappaB p65",
  "NFKB3"
]

{
  "chronos_mean_kmt2a_rearranged": -0.2156,
  "chronos_mean_other_leukaemia": -0.2752,
  "difference": 0.0595,
  "pan_essentiality_all_lines": -0.4057,
  "selectivity_rank": 15425,
  "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."
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "expressed_in": {
    "class": 1,
    "summary": "ubiquitous. RELA is a component of the classical NF-kB heterodimer and is expressed in essentially every nucleated cell; no cell-type-restricted expression claim is made or needed here.",
    "how_shown": "not measured in this beat; asserted as background, not as a finding"
  },
  "required_in": {
    "class": 2,
    "claim": "In MURINE MLL-AF9 myeloid leukaemia and human MLL-rearranged lines, RELA occupies the promoter regions of crucial MLL target genes and IKK/NF-kB signalling sustains the MLL-dependent LEUKAEMIA STEM CELL programme; suppressing NF-kB phenocopies loss of the functional MLL oncoprotein [E_q69_ct1].",
    "system_named_in_the_claim": "murine MLL-AF9 and human MLL-rearranged leukaemia cells - NOT infant B-lineage KMT2A::AFF1 (brief rule 73)",
    "pmids": [
      "24054986"
    ],
    "the_cell_type_is_a_STATE_not_a_LINEAGE": "the requirement reported is for the leukaemia-stem-cell compartment within an MLL-rearranged leukaemia, not for a lineage. That is a cell-STATE claim wearing cell-type clothing, and it is recorded in cell_state below as well as here."
  },
  "not_required_in": {
    "claim": "NO KMT2A-rearranged-SELECTIVE requirement is visible in this project's own genome-wide dependency scan. RELA sits in the ANTI-SELECTIVE half: Chronos -0.2156 in the 11 KMT2A-rearranged lines against -0.2752 in the 43 other leukaemia lines, difference +0.0595, selectivity rank 15,425 of 17,728.",
    "how_to_read_it": "a difference is not a dependency and this is not floor-compressed (pan-essentiality -0.4057, plenty of dynamic range), so the anti-selective placement is interpretable rather than uninterpretable. What it says is that a 21-day proliferation screen sees no EXTRA requirement for RELA in KMT2A-rearranged lines. It cannot see a differentiation block, a stem-cell-frequency phenotype, or an in vivo self-renewal requirement, which is exactly what PMID 24054986 measures.",
    "rescoping_this_forces": "the entry's NF-kB claim should be read as 'required for the LSC programme and for fusion retention on chromatin', which is what the paper shows, and NOT as 'KMT2A-rearranged cells need RELA more than other leukaemias do', which the scan contradicts."
  },
  "nodes": [
    "cell-state-stem-like-self-renewal",
    "cell-state-gmp-like"
  ],
  "context": "wild-type RELA in an MLL-fusion leukaemia; no measurement in normal human infant B-lymphopoiesis"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-stem-like-self-renewal"
    ],
    "claim": "In murine MLL-AF9 leukaemia, IKK/NF-kB signalling with RELA at MLL target promoters SUSTAINS the MLL-dependent leukaemia stem cell programme and is required for retention of both wild-type and fusion MLL protein on chromatin together with the associated histone modifications [E_q69_ct1].",
    "pmids": [
      "24054986"
    ],
    "system_named_in_the_claim": "murine MLL-AF9 myeloid leukaemia and human MLL-rearranged cell lines"
  },
  "regulates_state": {
    "note": "the state RELA maintains is a TRANSCRIPTIONAL-RETENTION state rather than a metabolic or cell-cycle one: the readout is fusion occupancy and H3K79/H3K4 retention, not proliferation index."
  },
  "bounded_query": {
    "date": "2026-09-21",
    "tool": "NCBI esearch db=pubmed",
    "query": "(\"NF-kappaB\" OR NFKB OR RELA OR p65)[tiab] AND (\"leukemia stem cell\" OR \"leukaemia stem cell\" OR \"leukemic stem cell\")[tiab] AND (MLL OR KMT2A)[tiab]",
    "count": 3,
    "on_topic_after_title_check": 1,
    "the_other_two": "PMID 41460961 is NUTM1-rearranged leukaemia and PMID 34877491 is TIFAB in MLL-AF9 - neither measures a RELA-dependent cell state.",
    "positive_control": "the bare operand RELA[tiab] AND (MLL OR KMT2A)[tiab] returns a non-zero count, and the joined query returns 3 rather than 0, so the instrument demonstrably returns a one (brief rule 67).",
    "bound": "titles and abstracts only; supporting figures not searched (brief rule 80)"
  },
  "confidence": "moderate",
  "caveats": "Every cell-state statement here is from ONE laboratory's 2013 paper in a murine MLL-AF9 system plus human MLL-rearranged lines. No infant KMT2A::AFF1 primary sample, no xenograft, no B-lineage measurement. The LSC claim is a functional-transplant claim in mouse; nothing here measures a human infant leukaemia stem cell. And the DepMap arm of this entry points the other way, which is recorded above rather than reconciled.",
  "counter_evidence": {
    "note": "This project's own genome-wide CRISPR scan places RELA 15,425th of 17,728 on KMT2A-rearranged selectivity, i.e. in the anti-selective half, with the KMT2A-rearranged arm LESS depleted than the comparator leukaemias. A 21-day proliferation screen and an in vivo LSC assay are different instruments measuring different things, and both results stand; but the entry must not be read as claiming a fusion-selective RELA dependency.",
    "citation": {
      "title": "DepMap KMT2A-selective dependency scan (this project, genome-wide, 11 KMT2A-rearranged vs 43 other leukaemia lines)",
      "url": "analyses/depmap-kmt2a-selective-scan-full/results.json",
      "type": "analysis"
    }
  }
}