Oncofusion

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Proteinweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q5-interactome5

KANSL2 - the second NSL subunit in the WDR5 structure, with one leukaemia record and a dependency profile that is the mirror image of a selective target

also called KANSL2 · C12orf41 · NSL2 · KAT8 regulatory NSL complex subunit 2

KANSL2 is one of the three proteins in the only solved structure of the NSL complex's WDR5-binding core. It is included here because that structure is the basis of the claim that NSL and the KMT2A-type complexes compete for WDR5 - and a claim about a structure should have entries for all the proteins in it.

The same thing, for a scientist

KANSL2 (Q9H9L4, 492 aa) is an NSL subunit that binds WDR5 directly and is the third protein in the KANSL1/WDR5/KANSL2 crystal structure on which this beat's WDR5-partition argument rests [E1]. It contributes a conserved linear motif to WDR5 alongside KANSL1's, and the same work establishes that WDR5's NSL and MLL/COMPASS interactions are mutually exclusive [E1]. Its own leukaemia literature is a single record: `(MLL OR KMT2A) AND (KANSL2 OR C12orf41 OR NSL2)` returns **1** [E2]. Its dependency profile is the opposite of a target: pan-essentiality -0.9807 across 1,208 lines with a KMT2A-rearranged difference of **+0.2265, rank 17,631 of 17,728 (99.45th percentile)**, and the lineage split shows the anti-dependency sitting overwhelmingly in the B-lineage arm (myeloid raw -0.687, z +0.41; **B-lineage z +1.32**) [E3][E4]. UniProt annotates one region with coordinates, **308-364, required for interaction with other NSL complex members** [E5].

What it looks like
KAT8 regulatory NSL complex subunit 2492 aa
NSL-subunit interaction regionNSL-subunit interaction region · residues 308–3640100200300400
loading AF-Q9H9L4-F1…
AlphaFold AF-Q9H9L4-F1 ↗
colourshape

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

very high (90+)confident (70–90)low (50–70)very low (<50)
I have never read one of these pictures before

A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.

Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.

Anything in yellow sticks is a bound small molecule, which is usually the drug.

Go deeper
Why a nearly-unstudied subunit gets its own entry

Because of the granularity rule and because of a specific failure mode this project has hit before: a complex-level claim gets written, and then nobody can check which subunit it actually rests on.

The WDR5-partition claim - that NSL and MLL/COMPASS cannot hold WDR5 at the same time - comes from a structure of three proteins: KANSL1, WDR5 and KANSL2 1. Two of those three now have entries in this graph (gene-wdr5 already existed, gene-kansl1 was written this cycle). Writing KANSL2 completes the structure, so that a reader who wants to interrogate the partition claim can reach every protein in it.

What the entry does not do is inflate KANSL2's importance. There is one leukaemia record 2, no functional leukaemia result, no cell-state or subnuclear data, and a dependency profile that points away from any target argument 3.

The B-lineage anti-dependency, and why it is reported rather than interpreted

KANSL2's split is unusually lopsided: myeloid z +0.41 but B-lineage z +1.32 4. A z of +1.32 means the B-lineage KMT2A-rearranged lines are more than one comparator standard deviation less dependent than other leukaemia lines.

This entry declines to interpret that. Four B-lineage index lines contribute, so one line can produce it; the pan-essentiality of -0.98 puts both arms in the compressed regime; and the standing rule that cross-gene z comparisons are not effect-size comparisons applies within a gene too, since the comparator SD sets the scale.

The number is recorded because the graph should be able to find it later if a pattern of B-lineage-specific anti-dependencies across NSL subunits ever emerges. Right now n = 1 pattern is not a pattern.

Cell type, cell state, localisation, epigenetics

Every axis is thin and this entry says so rather than padding.

  • Cell type: human cell lines for the biochemistry and crystallography; transgenic Drosophila for the in vivo requirement of the equivalent interaction 1. No haematopoietic system, no patient material.
  • Cell state: not established.
  • Subcellular: nucleus and mitochondrion per UniProt 5. The mitochondrial annotation is shared with KANSL1 and KANSL3 and is a genuine feature of this complex's literature, not a curation artefact of one entry.
  • Subnuclear: not established. NSL as a complex is promoter-associated, but nothing subnuclear is reported for KANSL2 specifically.
  • Epigenetic readout: none directly. KANSL2 has no catalytic activity; the complex it belongs to directs KAT8/MOF towards H4K5, K8 and K16 rather than K16 alone 6.
Facts and figures
uniprotQ9H9L4
gene symbolKANSL2
protein nameKAT8 regulatory NSL complex subunit 2
length AA492
alphafold IDAF-Q9H9L4-F1
accession resolutionUniProt REST query gene_exact:KANSL2 AND organism_id:9606 AND reviewed:true, run 2026-09-19; one reviewed hit; primary gene name read back as KANSL2 and length 492 confirmed from the same fetched record.
complexNSL (non-specific lethal)
domains noteOnly one UniProt region carries coordinates. The WDR5-binding conserved linear motif seen in PDB 4CY2 has no UniProt boundaries and was not derived from the structure in this cycle.
functionNSL complex subunit; contributes a conserved linear motif that binds WDR5
classificationNOT a documented interactor of KMT2A::AFF1; included to complete the KANSL1/WDR5/KANSL2 structure on which the WDR5-partition argument rests
interaction evidence classcrystallography (4CY2); proteomic purification
shown for fusionnone
cell type evidencehuman cell lines and transgenic Drosophila; no haematopoietic system
cell state evidencenot established
epigenetic readoutnone directly; the complex directs KAT8/MOF towards H4K5, K8 and K16 rather than K16 alone
PDB IDS
[
  "4CY2"
]
aliases retired or alternate
[
  "C12orf41",
  "NSL2"
]
complex partners
[
  "gene-kansl1",
  "gene-wdr5",
  "gene-kat8",
  "protein-nsl-complex"
]
domains
[
  {
    "name": "NSL-subunit interaction region",
    "start": 308,
    "end": 364
  }
]
localization
{
  "subcellular": "nucleus; mitochondrion (UniProt)",
  "subnuclear": "not established"
}
essentiality
{
  "depmap_scan": "analyses/depmap-kmt2a-selective-scan-full",
  "pan_essentiality_all_lines": -0.9807,
  "n_all_lines": 1208,
  "mean_kmt2a_rearranged": -0.7436,
  "mean_other_leukemia": -0.97,
  "kmt2a_selectivity_difference": 0.2265,
  "rank": 17631,
  "n_scanned": 17728,
  "percentile": 99.453,
  "lineage_split": {
    "analysis": "analyses/depmap-interactome5-lineage-split",
    "raw_mean_kmt2a_myeloid": -0.687,
    "z_kmt2a_myeloid": 0.41,
    "z_kmt2a_b_lineage": 1.32,
    "z_OCI_AML3": -0.97,
    "z_U937": 0.67,
    "n_kmt2a_b_lineage_lines": 4,
    "verdict": "weak or ambiguous; large positive z in a four-line arm, reported and not interpreted"
  },
  "interpretation": "anti-selective and compressed; no target argument"
}
enumeration record counts
[
  {
    "query": "(MLL OR KMT2A) AND (KANSL2 OR C12orf41 OR NSL2)",
    "records": 1
  },
  {
    "query": "(MLL OR KMT2A) AND (KANSL3 OR KIAA1310 OR NSL3)",
    "records": 0
  },
  {
    "date": "2026-09-19"
  }
]
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.7436,
  "chronos_mean_other_leukaemia": -0.97,
  "difference": 0.2265,
  "pan_essentiality_all_lines": -0.9807,
  "selectivity_rank": 17631,
  "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
  • KANSL2 is broadly required (-0.98 across 1,208 lines) with an anti-selective KMT2A profile. Nothing here supports it as a target and this entry exists for structural completeness.
  • If the WDR5 partition is real, weakening NSL's grip on WDR5 could increase WDR5 supply to SET1/MLL complexes - the wrong direction in this disease. Any NSL-directed idea has to confront that before it is worth testing.
  • The mitochondrial annotation shared across KANSL1, KANSL2 and KANSL3 means NSL perturbation is not a purely chromatin perturbation, and a viability phenotype could arise from metabolism rather than transcription.
Still open
  1. Does removing KANSL2 alone release WDR5 to SET1/MLL complexes, or is KANSL1 the limiting motif? The structure shows both contribute motifs; no separation-of-function experiment exists.
  2. Why is KANSL2's anti-dependency three times stronger in the B-lineage arm than the myeloid arm, when KANSL3 shows nothing of the kind? Most likely a single-line artefact, and that is checkable line by line.
  3. What are the residue boundaries of the KANSL2 WDR5-binding motif? They are derivable from PDB 4CY2 and would give this entry a meaningful domain lane, which it currently lacks.
Every source behind this entry (6)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    KANSL1 acts as a scaffold interacting with four other NSL subunits including WDR5, which in turn binds KANSL2; the KANSL1/WDR5/KANSL2 structure shows WDR5 is recruited into the NSL complex via conserved linear motifs of KANSL1 and KANSL2; and the interactions of WDR5 with the MOF-containing NSL complex and with MLL/COMPASS histone methyltransferase complexes are mutually exclusive.

    Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex · Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A · Genes & Development 28(9):929-42 2014
    PMID 24788516DOI
    What this evidence cannot show

    Abstract fetched from PubMed and read on 2026-09-19; full text not read, identifiers copied from that fetched record. Crystallography plus Drosophila genetics. **The functional in vivo tests in this paper are of KANSL1 mutants, not KANSL2 mutants**, so KANSL2's contribution to assembly and targeting is established structurally and by inference from the complex, not by its own loss-of-function experiment.

    Evidence that argues against this (1)
    • Reading 'KANSL2 is in the structure' as 'KANSL2 is required for the partition' would be the argument-from-presence this project has criticised elsewhere. The structure shows KANSL2 contributes a WDR5-binding motif; whether removing KANSL2 alone releases WDR5 is untested. Cai Y et al. 2010
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    As of 2026-09-19 PubMed returns 1 record for '(MLL OR KMT2A) AND (KANSL2 OR C12orf41 OR NSL2)' and 0 for '(MLL OR KMT2A) AND (KANSL3 OR KIAA1310 OR NSL3)'. KANSL2 has no functional leukaemia literature.

    What this evidence cannot show

    Count from the esearch `count` field, queried 2026-09-19. Symbol set searched: KANSL2, C12orf41, NSL2, and separately KANSL3, KIAA1310, NSL3. Not searched as phrases: 'KAT8 regulatory NSL complex subunit 2'. The alias NSL2 is short and could collide, so this count is an upper bound on relevance as well as a floor on recall.

    Evidence that argues against this (1)
    • A subunit-symbol enumeration would report the whole NSL complex as having no leukaemia literature, which is wrong - the NUP98 result is reachable only through complex-name phrase queries. A zero or one on a subunit symbol says nothing about the complex. Xu H et al. 2016
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    In the genome-wide KMT2A-rearranged selectivity scan of 17,728 genes, KANSL2 has a pan-essentiality of -0.9807 across 1,208 lines and a KMT2A-rearranged selectivity difference of +0.2265 (KMT2A-rearranged mean -0.7436 against other-leukaemia mean -0.97), ranking 17,631 (99.453rd percentile).

    Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap Chronos via Open Targets) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026
    What this evidence cannot show

    Row read out of analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-19 in a scripted pass. Eleven KMT2A-rearranged against 43 other leukaemia lines, AML-heavy, none infant-derived. At a pan-essentiality near -1 the difference statistic is compressed and its sign is not reliable evidence of protection.

    Evidence that argues against this (1)
  4. E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.database

    On the lineage-split run for this beat, KANSL2's anti-dependency is concentrated in the B-lineage arm: KMT2A-rearranged myeloid raw mean gene effect -0.687 (z +0.41 in other-leukaemia SDs) against KMT2A-rearranged B-lineage z +1.32, with OCI-AML3 at z -0.97 and U-937 at z +0.67. The verdict recorded by the run is 'weak or ambiguous'.

    Interactome round 5 panel, lineage-split DepMap dependency (FACT, NSL, MSL, COMPASS remainder, Mediator) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-interactome5-lineage-split 2026
    What this evidence cannot show

    Rows read from analyses/depmap-interactome5-lineage-split/results.json on 2026-09-19. **Four B-lineage index lines contribute, so a single line can generate a z of this size**, and the split is by lineage LABEL rather than expression signature. This entry reports the number and explicitly declines to interpret it.

    Evidence that argues against this (1)
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB Q9H9L4 (KANL2_HUMAN, KAT8 regulatory NSL complex subunit 2) is 492 aa with synonyms C12orf41 and NSL2, is annotated to nucleus and mitochondrion, appears in one PDB entry (4CY2), and carries one annotated region with residue coordinates: aa 308-364, required for interaction with other NSL complex members.

    UniProtKB Q9H9L4 (KANL2_HUMAN), KAT8 regulatory NSL complex subunit 2 · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
    What this evidence cannot show

    Record fetched 2026-09-19 via UniProt REST with gene_exact:KANSL2 AND organism_id:9606 AND reviewed:true; **primary gene name read back as KANSL2 and length 492 confirmed from the same fetched record**, per the standing accession rule. One reviewed hit. The WDR5-binding linear motif described in the crystal structure has no UniProt coordinates and is deliberately not given a domain lane.

    Evidence that argues against this (1)
    • Only one region has coordinates across 492 residues, so the domain lane this entry contributes is minimal. Deriving the WDR5 motif boundaries from the PDB entry 4CY2 would be possible but was not done in this cycle, and inventing them was not an option. Dias J et al. 2014
  6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The NSL complex is composed of nine subunits and assembly of MOF into MSL versus NSL controls its substrate specificity: MSL-associated MOF acetylates nucleosomal H4 almost exclusively on K16, whereas NSL-associated MOF also acetylates H4 on K5 and K8.

    Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex · Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC · Journal of Biological Chemistry 285(7):4268-72 2010
    PMID 20018852DOI
    What this evidence cannot show

    Abstract fetched from PubMed and read on 2026-09-19; full text not read, identifiers copied from that fetched record. Substrate specificity measured on nucleosomal substrates in vitro; in vivo mark distribution may differ. This citation is used here for complex composition and mark specificity, not for anything about KANSL2 individually.

    Evidence that argues against this (1)
    • The complex's composition has been redefined more than once since 2010 and subunit rosters differ between preparations, so 'nine subunits' should be read as the roster from one proteomic study rather than a settled number. Dias J et al. 2014
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