CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse

{
  "bait": "MLL-AF4 (= KMT2A::AFF1)",
  "p_value": 0.0116,
  "spectral_counts": "7|9",
  "n_fusions_of_seven": 7,
  "negative_control_counts": "2|2",
  "per_bait": {
    "MLL-AF1p": "0.00582 (9|8)",
    "MLL-AF4": "0.0116 (7|9)",
    "MLL-AF9": "2.26e-09 (33|32)",
    "MLL-CBP": "0.000352 (8|29)",
    "MLL-EEN": "8.89e-06 (28|34)",
    "MLL-ENL": "7.89e-10 (34|34)",
    "MLL-GAS7": "0.00684 (20|17)"
  },
  "source": "analyses/skucha-mll-fusion-interactome/results.json, re-derived from the cached MOESM4 xlsx on 2026-09-21"
}

[
  "Jurkat (human T-ALL) - AP-MS host",
  "MLL/AF4-positive cell models - CHD4 perturbation induces myeloid gene expression",
  "human MLL/AF4 pro-B ALL patients relapsing as AML - recurrent CHD4 alteration",
  "childhood AML lines, primary childhood AML blasts and a PDX - CHD4 required for maintenance",
  "AML blasts - CHD4 depletion sensitises to daunorubicin and cytarabine",
  "normal bone marrow / non-transformed haematopoietic cells - spared"
]

{
  "query": "CHD4[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab])",
  "querytranslation": "\"CHD4\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract])",
  "count": 3,
  "on_topic_after_title_check": 1,
  "date": "2026-09-21",
  "tool": "NCBI esearch db=pubmed",
  "positive_control": "the identical query shape with MEN1 returns 85",
  "rejected": "PMID 32341405 (congenital heart disease connectome) and PMID 31221981 (IDH1/2-KDM5C-KDM6A review) are off-beat; the single on-topic record is PMID 35839448.",
  "reading": "One on-topic record - and it happens to be in the index fusion."
}

{
  "_added": "king, cycle 48, 2026-09-21. analyses/mll-fusion-interactome-complexes/run.py",
  "what_this_adds": "Q84's caution in this entry is literally correct and its inference is now testable. It said no other subunit of either remodelling complex is named anywhere in the PAPER'S BODY TEXT -- true. But the paper's own supplementary table is data, and it contains five NuRD subunits and six BAF subunits. The complex-level claim the body text could not support, the table does.",
  "measured_in_the_960_protein_network": {
    "NuRD": "5 of 14 subunits: CHD3, CHD4, GATAD2A, GATAD2B, MBD2. Hypergeometric p = 3.5e-4 against a 20,000 proteome; 0.67 expected by chance. Median 5 of 7 baits.",
    "BAF_SWI_SNF": "6 of 17 subunits: PBRM1, SMARCA4, SMARCB1, SMARCC1, SMARCC2, SMARCE1. p = 9.4e-5; 0.82 expected. Median 5 of 7 baits."
  },
  "so_the_conclusion_changes_but_only_partly": "Neither complex is represented by a lone core component. Both bring several subunits, including CHD3 alongside CHD4 and SMARCC2 alongside SMARCC1. That is what a genuine complex-level association looks like and it is not what a single sticky protein looks like.",
  "the_reason_to_still_resist_the_story": "The single strongest complex signature in the whole analysis is the CCT/TRiC chaperonin, 8 of 9 subunits at p = 2.4e-10 -- a canonical affinity-purification contaminant that nobody believes is a specific partner. So complex-wide enrichment is NOT by itself evidence of specific binding, and the NuRD and BAF rows sit two to six orders of magnitude BELOW that artifact. The positive control behaves correctly (SEC, 10 of 16, p = 3.8e-10, with zero pan-fusion members because its members ARE the bait partners), which licenses reading the ranking -- but the original caution about orthogonal validation stands undiminished.",
  "background_caveat": "The background is the ~20,000-protein proteome, not the 4,600 proteins the study actually recovered before filtering, which is not in the table. That inflates every p-value for any complex of abundant nuclear proteins. The ranking is the result; the absolute p-values are an upper bound on significance.",
  "CORRECTION_per_bait_2026_09_21": {
    "what_i_got_wrong": "Earlier today I added the pooled complex figures to this entry and used them to withdraw this entry's 'lone core subunit' caution. Running the SAME analysis PER BAIT reverses that for the index fusion. The pooled number is a union over seven baits and is not a statement about MLL-AF4.",
    "in_the_MLL_AF4_column": {
      "complex": "NuRD",
      "detail": "1 of 14 subunits in the MLL-AF4 column: CHD4 ALONE (p<0.05). The 5-subunit NuRD signature I cited is the union over all seven baits -- MLL-AF9 and MLL-EEN contribute 4 each, MLL-AF4 contributes one."
    },
    "so_the_original_caution_STANDS_for_the_index_fusion": "The entry's argument was about what the data support for KMT2A::AFF1, and per-bait it is right. My withdrawal was correct about the 960-protein network and wrong about the column that matters. The edge in data/graph/edges/king-cycle48.json marked 'refutes' overstates it and is qualified there.",
    "what_survives_per_bait": "HBO1/KAT7 holds up in the MLL-AF4 column at 4 of 10 subunits (BRPF1, JADE2, JADE3, KAT7) with 3 at p<0.05, and CPSF/3'-end at 4 of 12 with 2 significant. The contaminant control is undiminished per-bait: CCT/TRiC is 8 of 9 in the MLL-AF4 column with 6 significant.",
    "the_per_bait_positive_control": "SEC is 10/16 in MLL-AF4 and 10/16 in MLL-AF9 but 0/16 in MLL-AF1p and MLL-EEN, 1/16 in MLL-CBP and MLL-GAS7, 2/16 in MLL-ENL. Those two baits are exactly the fusions whose C-terminal partners are SEC components. The per-bait method recovers that correctly, which is what licenses reading the other rows per-bait."
  }
}

{
  "_added": "king, cycle 48, 2026-09-21, after Q86 flagged that cycle-47 entries understate the record. Verified by me directly from the supplementary file, not from the paper's prose.",
  "screened": true,
  "library_symbol": "CHD4",
  "shrnas_for_this_gene": 6,
  "design": "Supplementary Table 6 / MOESM5 is 768 data rows, 128 unique gene symbols, EXACTLY 6 shRNAs each -- counted with openpyxl on 2026-09-21. Negative-selection RNAi screen in MLL-AF9-expressing MOLM-13.",
  "what_this_DOES_establish": "Every one of the 128 conserved MLL-fusion interactors, this protein included, was functionally tested against an MLL fusion. An entry saying 'nothing in the paper validates this prey' is true of BINDING and understates the record.",
  "what_this_does_NOT_establish": "A per-gene result. Scores are presented as heatmaps (Fig. 2c/2d) and no per-gene depletion value is tabulated, so for any individual gene the outcome is measured-not-reported. It is also MLL-AF9 MOLM-13, a myeloid line, not the index fusion and not B-lineage.",
  "absence_class_for_the_per_gene_score": "measured-not-reported"
}