MSL1 - the MSL scaffold that carries MOF and MSL2 to HOXA9 and MEIS1, with zero records against KMT2A and a mapped, drawable domain architecture

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.

• MSL1 is barely required anywhere (pan -0.365) and shows no KMT2A selectivity, so there is no genetic argument for it as a target and this entry makes none.
• Because MOF is shared between MSL and NSL, any MOF-directed agent hits both assemblies, and the two write different marks. A programme aiming at 'the MOF complex' would be aiming at two complexes with different outputs and different partners.
• If H2BK34 ubiquitylation is conditional on prior nucleosome alteration, then an MSL-directed intervention would only act where that alteration already occurs - which could make efficacy depend on chromatin state in a way that is hard to predict or dose against.
• MSL1 carries two nuclear localisation signals and a nuclear-speckle annotation; a degrader would perturb whatever speckle-associated function that reflects, which nobody has characterised.

1. Does perturbing MSL1 - rather than MOF, which sits in both complexes - affect KMT2A-fusion target gene expression? No published experiment perturbs an MSL-specific scaffold in a leukaemia model, so the MSL contribution to the MOF phenotype is entirely undetermined.
2. Is H2BK34ub present at HOXA9 and MEIS1 in KMT2A-rearranged cells, and does it require MSL1? The activity is reported important at those loci in cells without a fusion; nobody has looked in cells with one.
3. Does the contested nucleosomal efficiency of MSL1/2 resolve in favour of a conditional reaction - one that needs the nucleosome altered first? If so, the relevant question becomes what alters it, which would connect this entry to the histone-chaperone machinery written elsewhere in this beat.
4. Why is MSL1 annotated to nuclear speckles? A splicing-factor compartment is an unexpected address for an H4K16ac scaffold and the annotation has not been checked against its primary source here.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Structures of binary complexes of mammalian MSL3 and the histone acetyltransferase MOF with consecutive segments of MSL1 show MSL1 interacts with MSL3 as an extended chain forming an extensive hydrophobic interface, while the MSL1-MOF interface involves electrostatic interactions between the HAT domain and a long helix of MSL1; MOF makes analogous interactions with NSL1. In Drosophila, selective disruption of Msl1 interactions with Msl3 or Mof severely affects Msl1 targeting to the bodies of dosage-compensated genes and to several high-affinity sites without affecting promoter binding.

   Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1 · Kadlec J, Hallacli E, Lipp M, Holz H, Sanchez-Weatherby J, Cusack S, Akhtar A · Nature Structural & Molecular Biology 18(2):142-9 2011
   PMID 21217699DOI
   ▸What this evidence cannot show

   Abstract fetched from PubMed and read on 2026-09-19; full text not read, every identifier copied from that fetched record. Crystallography of **binary** complexes with MSL1 segments, not of the intact complex. The in vivo targeting experiments are in **Drosophila dosage compensation**, a specialised system whose mammalian counterpart is not X-restricted; the transfer to human MSL1 is architectural and is labelled as such. The statement about MOF-NSL1 is made in this paper and is consistent with both scaffolds carrying a PEHE domain.

   ▸Evidence that argues against this (1)

   • Because MOF binds MSL1 and KANSL1 through analogous interactions, a MOF-directed intervention cannot distinguish the two complexes, and every leukaemia experiment in this area perturbs MOF rather than a scaffold. The complex assignment of the published MLL-AF9 phenotype is therefore unresolved. Valerio DG et al. 2017
2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   MSL2 in the MOF-MSL complex is a histone ubiquitin E3 ligase that, together with MSL1, ubiquitylates nucleosomal H2B on lysine 34; H2BK34ub directly regulates H3K4 and H3K79 methylation through trans-tail crosstalk in vitro and in cells; and MSL1/2 activity is important for transcription activation at the HOXA9 and MEIS1 loci. The MOF-MSL complex therefore carries two distinct chromatin-modifying activities, H4K16 acetylation and H2BK34 ubiquitylation.

   The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3 K4 and K79 methylation · Wu L, Zee BM, Wang Y, Garcia BA, Dou Y · Molecular Cell 43(1):132-44 2011
   PMID 21726816DOI
   ▸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. **The original abstract describes the activity as 'robust'; that word is not used in this entry's own voice because an independent reinvestigation contradicts it on nucleosomal substrates (E3).** Human cell lines with no KMT2A fusion; the HOXA9/MEIS1 result is a knockdown/activation result, not a fusion-context result. Trans-tail crosstalk with H3K4 and H3K79 is exactly the kind of in-vitro-plus-cells claim that has proved fragile elsewhere in this graph.

   ▸Evidence that argues against this (1)

   • Purified MSL1/MSL2 ubiquitylate free histone substrates efficiently but modify nucleosomes very poorly, which implies efficient H2BK34 ubiquitylation requires the nucleosome to be structurally altered first. That reframes MSL1/2 as a conditional rather than a constitutive nucleosomal ligase and is the reason this entry avoids the word 'robust'. Krajewski WA et al. 2019
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Purified MSL1/MSL2 efficiently ubiquitylate free histone substrates but very poorly modify nucleosomes, implying a requirement for nucleosome structural alteration for efficient H2BK34 ubiquitylation; H2B ubiquitylation by MSL1/2 depends on substrate configuration, and gel-shift analysis suggests MSL1/2 can deposit two ubiquitin moieties in one nucleosome.

   Analysis of histone ubiquitylation by MSL1/MSL2 proteins in vitro · Krajewski WA, Vassiliev OL · Archives of Biochemistry and Biophysics 666:22-30 2019
   PMID 30930284DOI
   ▸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. **Purely in vitro with purified proteins and reconstituted nucleosomes** - a negative in vitro result can reflect a missing cofactor or a non-physiological configuration rather than the absence of the activity in cells. This is one reinvestigation, not a body of replication.

   ▸Evidence that argues against this (1)

   • The original report demonstrated the activity both in vitro and in cells and tied it to transcription at HOXA9 and MEIS1, which an in vitro nucleosome assay cannot overturn. The correct summary is that the efficiency of the nucleosomal reaction is contested, not that the activity is refuted - and this entry states it that way. Wu L et al. 2011
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProtKB Q68DK7 (MSL1_HUMAN, Male-specific lethal 1 homolog) is 614 aa with the synonym MSL1L1; it is annotated to nucleus, nucleoplasm and nuclear speck; it has three PDB cross-references (4B7Y, 4B86, 4DNC); and it carries a coiled coil at 213-282, a region interacting with MSL2 at 223-237, a PEHE domain at 472-591, a region interacting with the KAT8 HAT domain at 496-514, a region sufficient for interaction with the MSL3 MRG domain at 550-591, a nuclear localisation signal at 317-346 and a bipartite nuclear localisation signal at 505-519.

   UniProtKB Q68DK7 (MSL1_HUMAN), Male-specific lethal 1 homolog · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
   ▸What this evidence cannot show

   Record fetched 2026-09-19 via UniProt REST with gene_exact:MSL1 AND organism_id:9606 AND reviewed:true; **primary gene name read back as MSL1 and length 614 confirmed from the same fetched record**, per the standing accession rule. One reviewed hit - worth stating explicitly because the brief flagged MSL1 as short and collision-prone, and it is: MSL1 is also used for the unrelated KANSL1 under its old name MSL1v1. All seven boundaries are copied from the fetched feature table; none is estimated.

   ▸Evidence that argues against this (1)

   • The nuclear-speck annotation comes from UniProt curation of a literature this entry did not read, and a speckle localisation for an H4K16ac scaffold is unexpected enough that it should be treated as an annotation to verify rather than a mechanistic fact. Kadlec J et al. 2011
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   As of 2026-09-19, PubMed returns 0 records for '(MLL OR KMT2A) AND (MSL1 OR KIAA1585 OR MSL-1 OR hMSL1)', 0 for '(MLL OR KMT2A) AND MSL1', and 1 for 'MSL1 AND (leukemia OR leukaemia)', which on title-check is a DNA/HDAC dual-targeting anticancer compound paper and not an MSL1 study. '(MLL OR KMT2A) AND (MSL3 OR MSL3L1)' returns 1.

   PubMed E-utilities esearch record counts for MSL1 and the MSL complex against KMT2A, MLL and leukaemia, run for interactome round 5 · NCBI PubMed, queried 2026-09-19 2026
   ▸What this evidence cannot show

   Counts from the esearch `count` field, queried 2026-09-19, with the single leukaemia hit title-checked. Symbol set searched: MSL1, KIAA1585, MSL-1, hMSL1, MSL1L1 was not searched separately. **Two zero-returning queries are more reassuring than one**, but a counted absence is a floor on recall, and MSL1 papers written about 'the MSL complex' without the subunit symbol would be missed - the same failure that would have hidden the NUP98/NSL result had only subunit symbols been searched.

   ▸Evidence that argues against this (1)

   • The MSL1-relevant leukaemia evidence in this entry comes entirely from papers that do not mention MLL or KMT2A - the H2BK34 study reaches HOXA9 and MEIS1 without a fusion anywhere in it. A zero count here therefore understates the gene's relevance rather than settling it, which is the opposite of how a counted absence usually behaves. Wu L et al. 2011
6. E6moderate 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, MSL1 has a pan-essentiality of -0.3654 across 1,208 lines and a KMT2A-rearranged difference of -0.0728 (KMT2A-rearranged mean -0.4488 against other-leukaemia mean -0.376), ranking 2,078 (11.722nd percentile). MSL2 is -0.0154 at rank 7,112 and MSL3 is -0.1615 at rank 408 on a pan-essentiality of +0.0179.

   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

   Rows 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. **A difference of -0.0728 is well inside noise**, and the 11th-percentile rank sounds meaningful and is not, because ranks compress hard near the centre of the distribution. MSL3's rank of 408 on a positive pan-essentiality is the most interesting number in this row and is still only -0.1615.

   ▸Evidence that argues against this (1)

   • The three MSL subunits span ranks 408, 2,078 and 7,112 despite forming one complex, which is the same within-complex spread seen for FACT and NSL and is a property of the statistic rather than of the biology. Broad Institute DepMap / Open Targets Platform; analyses/depmap-interactome5-lineage-split 2026
7. E7weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.database

   On the lineage-split run for this beat, MSL1 shows a small requirement in both lineage halves and is classified 'weak or ambiguous': KMT2A-rearranged myeloid z -0.27, B-lineage z -0.42, OCI-AML3 z -0.71, U-937 z +1.07, on a pan-essentiality of -0.365. MSL3 in the same run is myeloid z -1.03 and B-lineage z -0.40.

   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. Six myeloid and four B-lineage index lines, so a single line moves a mean; the split is by lineage LABEL rather than expression signature. **Both halves being negative is the shape a genuine dependency has, but at z -0.27 and -0.42 on a pan-essentiality of -0.365 these are small numbers on a gene barely required anywhere**, and nothing should be built on them.

   ▸Evidence that argues against this (1)

   • MSL3's myeloid z of -1.03 against a B-lineage z of -0.40 is the asymmetric shape that this beat's brief warns is produced for free by a myeloid-enriched index panel. It is recorded and not pursued. Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026
8. E8strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Assembly of MOF into the MSL versus the NSL complex controls its substrate specificity: MSL-associated MOF acetylates nucleosomal histone H4 almost exclusively on lysine 16, whereas NSL-associated MOF has relaxed specificity and also acetylates H4 on lysines 5 and 8.

   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. Specificity measured on nucleosomal substrates in vitro; in vivo mark distribution may differ. This is the load-bearing fact for treating MSL and NSL as different things rather than as 'the MOF complex'.

   ▸Evidence that argues against this (1)

   • If the in vitro specificity does not hold in cells, then H4K16ac would not discriminate MSL from NSL activity and much of the reasoning in this entry pair would lose its readout. No in vivo test of the discrimination was found in this beat. Valerio DG et al. 2017
9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   MOF's histone acetyltransferase activity is required for MLL-AF9 leukaemogenesis: conditional Mof deletion reduced tumour burden and prolonged survival, catalytically inactive MOF failed to rescue, a MYST inhibitor blocked growth of murine and human MLL-AF9 lines, and Mof inactivation also suppressed leukaemia development in an NUP98-HOXA9 model.

   Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis · Valerio DG, Xu H, Chen CW, Hoshii T, Eisold ME, Delaney C, Cusan M, Deshpande AJ, Huang CH, Lujambio A, Zheng YG, Zuber J, Pandita TK, Lowe SW, Armstrong SA · Cancer Research 77(7):1753-1762 2017
   PMID 28202522DOI
   ▸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. **MOF is the catalytic subunit of both MSL and NSL, so this experiment removes the enzyme from both complexes at once and cannot be assigned to MSL.** MLL-AF9 and murine models, not KMT2A::AFF1 and not human infant disease.

   ▸Evidence that argues against this (1)

   • This is cited in this entry specifically to mark what is NOT known: no published experiment perturbs MSL1 or any MSL-specific scaffold in a leukaemia model, so the MSL contribution to the MOF phenotype is entirely undetermined. Kadlec J et al. 2011

• binds →MSL2 — the second H2B ubiquitin ligase, sitting inside the MOF complex the KMT2A fragment contacts

  MSL1 binds MSL2 through residues 223-237 and is required with it for H2BK34 ubiquitylation.

• binds →KAT8 (MOF) — a genuine KMT2A partner that binds the half of KMT2A the fusion discards

  MSL1 PEHE domain binds the KAT8 HAT domain at residues 496-514; MOF makes analogous contacts with KANSL1.

• related to →KANSL1 - the NSL scaffold, and the protein through which WDR5 binding to NSL and to MLL/COMPASS is mutually exclusive

  Parallel scaffolds: both use a PEHE domain to hold MOF, and the complex they build determines whether MOF writes H4K16ac alone or also H4K5ac and H4K8ac.

• related to →The fusion may reach the H2B ubiquitin mark through MOF-MSL rather than through RNF20/RNF40 — the one configuration in which this layer could be selective

  Supplies the missing scaffold subunit for the hypothesis that the fusion reaches H2Bub through MOF-MSL rather than RNF20/RNF40.

• regulates →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  MSL1/2 activity is reported important for transcription activation at the HOXA9 locus - in cells without a KMT2A fusion.

• regulates →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  MSL1/2 activity is reported important for transcription activation at the MEIS1 locus - in cells without a KMT2A fusion.