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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q39-acetylation-cycle

HDAC1 - a class I eraser that has no dependency claim of its own in this disease, because removing it alone does nothing until HDAC2 goes too

also called HD1 · RPD3L1 · GON-10 · histone deacetylase 1

HDAC1 is one of the main eraser enzymes that pull acetyl tags off histones. In leukaemia cells it turns out that switching HDAC1 off by itself achieves very little - its near-twin HDAC2 simply covers for it - and only removing both together kills the cells.

The same thing, for a scientist

HDAC1 (Q13547, 482 aa) is a class I deacetylase and the catalytic subunit of the Sin3, NuRD and CoREST corepressor complexes. This graph gets one entry per thing, so HDAC1 gets its own; what the entry has to record is that **the thing does not have its own result**. In the only functional-genetic dissection of individual HDACs in an MLL-fusion malignancy, **genetic co-depletion of Hdac1 with Hdac2 was pro-apoptotic in Emu-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233**, while it was **Hdac3** depletion that was selected against in all three tumour types including MLL-AF9;Nras AML [E1]. The load-bearing word is *co-depletion*: HDAC1 and HDAC2 are functionally redundant paralogues here, and a single-gene perturbation of either one is not the experiment. That is the mirror of the paralogue problem this graph recorded from the other direction in `ana-the-acetyltransferase-signal-is-paralogue-specific-and-does-not-survive-pan-essentiality`, where selectivity split *between* near-identical paralogues with rank spreads in the thousands. Here it does the opposite - the paralogues buffer each other and neither shows an effect alone. **Both patterns defeat a single-gene readout, in opposite directions, and neither is visible unless the paralogue is tested at the same time.** Clinically, HDAC1 is inhibited by every agent in this beat - vorinostat, panobinostat, romidepsin, chidamide and belinostat all cover it [E2] - so no HDAC-inhibitor result in this disease can be attributed to HDAC1, and none is.

Go deeper
What is and is not known about HDAC1 here

Known:

  • HDAC1 is inhibited by all the clinically used agents in this disease 2.
  • HDAC1 and HDAC2 must be depleted together to produce a pro-apoptotic response, and the HDAC1/2-selective compound RGFP233 reproduces the genetic result 1. A selective chemical tool for the pair therefore exists.
  • Combined HDAC1-3 knockdown in an MLL-AF4 context relieves an inhibitory function of wild-type MLL and overrides the fusion's dominant effect at the ALOX5 promoter 3 - but that experiment knocked down all three class I enzymes together and attributes to none of them.

Not known:

  • Whether HDAC1/2 co-depletion kills KMT2A-fusion cells. The co-depletion result is in Emu-Myc lymphoma; the MLL-AF9 arm of the same paper produced the HDAC3 finding 1. This is a real gap and the paper is the obvious place to close it.
  • Whether the paralogue buffering is quantitative (total HDAC1+HDAC2 dose) or qualitative (distinct complexes).
  • Any fusion-directed function. HDAC1 has no reported physical or functional relationship to a KMT2A fusion protein found in this beat.

A note on the granularity rule. Writing a single entry for 'class I HDACs' would have hidden exactly the fact this entry exists to state - that the class contains one enzyme with a genuine individual result (HDAC3) and a redundant pair without one. One entry per thing is what makes the asymmetry visible.

Facts and figures
uniprotQ13547
length AA482
gene symbolHDAC1
accession resolutiongene_exact:HDAC1 AND organism_id:9606 AND reviewed:true returned exactly 1 reviewed row; primary gene name read back as HDAC1 (rule 62 applied).
classclass I histone deacetylase; catalytic subunit of the Sin3, NuRD and CoREST corepressor complexes
individual dependency claimfalse
why no individual claimfunctionally redundant with HDAC2; only co-depletion of Hdac1 with Hdac2 produced a pro-apoptotic response
redundant partnergene-hdac2
selective tool for the pairRGFP233 (HDAC1/2-selective)
co depletion tested inEmu-Myc lymphoma - NOT in the MLL-AF9;Nras arm of the same study
kmt2a fusion specific functionnone reported
attribution possible from pharmacologyfalse
paralogue lessonHDAC1/HDAC2 buffer each other so neither shows an effect alone; the HBO1/MOZ acetyltransferase paralogues in this graph do the opposite, with one member carrying all the signal. Both defeat a single-gene readout, in opposite directions.
covered by clinical agents
[
  "vorinostat",
  "panobinostat",
  "romidepsin",
  "chidamide",
  "belinostat"
]
essentiality
{
  "depmap_common_essential": null,
  "note": "DepMap not queried in this beat. A single-gene DepMap score is structurally uninformative for a buffered paralogue pair, which is worth stating before anyone runs one."
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.0726,
  "chronos_mean_other_leukaemia": -0.1752,
  "difference": 0.1026,
  "pan_essentiality_all_lines": -0.1323,
  "selectivity_rank": 16942,
  "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
  • Because HDAC1 and HDAC2 buffer each other, a clinically useful effect needs both engaged simultaneously - which means the therapeutic window is set by the more toxic of the two engagements, not by the more selective one.
  • HDAC1 sits in Sin3, NuRD and CoREST, three corepressor complexes with distinct and essential roles across development. Inhibiting the catalytic subunit does not let a drug choose among them, and in an infant all three are in active use.
  • This graph's single-gene dependency instruments - DepMap scans, CRISPR screens - are structurally blind to a buffered paralogue pair. Any conclusion that 'HDAC1 is not a dependency' drawn from such a scan would be an artefact of the assay, not a finding.
  • The only MLL-AF4 class I result runs through the wild-type KMT2A allele, so it inherits the allele-directed vulnerability recorded for silmitasertib: loss of the wild-type copy defeats it with no drug-binding-site mutation required.
Still open
  1. Does HDAC1/HDAC2 co-depletion kill KMT2A-fusion cells? The co-depletion result is in Emu-Myc lymphoma and the same paper's MLL-AF9 arm produced a different answer, so the experiment that would settle this was run in the wrong arm.
  2. Is the redundancy quantitative - a total HDAC1+HDAC2 dose - or qualitative, with the two enzymes in distinct complexes that can substitute? An HDAC1 knock-in that cannot enter NuRD would separate them.
  3. Because a single-gene CRISPR screen cannot see a buffered pair, how many other redundant-paralogue dependencies in this disease are invisible to the DepMap-style instruments this graph relies on?
  4. Does HDAC1 have any physical relationship to a KMT2A fusion protein? Nothing was found in this beat, and nobody appears to have looked.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In a functional-genetic dissection of individual Hdacs across three murine malignancies including MLL-AF9;Nras(G12D) AML, genetic co-depletion of Hdac1 with Hdac2 was pro-apoptotic in Emu-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233, whereas it was Hdac3 depletion that caused cells to be selected against in competitive assays for all three tumour types.

    Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. · Matthews GM, Mehdipour P, Cluse LA, Falkenberg KJ, Wang E, Roth M, et al. · Blood 126(21):2392-2403 2015
    PMID 26447190DOI
    What this evidence cannot show

    The co-depletion result is reported in Emu-Myc lymphoma, NOT in the MLL-AF9;Nras arm, so this entry does not claim HDAC1/2 co-depletion kills KMT2A-fusion cells - only that the paralogue redundancy is established in a leukaemia/lymphoma setting by this design. Mouse models, shRNA depletion rather than knockout, so residual protein remains. Only the abstract was read; PMCID PMC4653767, full text not fetched in this beat.

    Evidence that argues against this (1)
    • This graph's acetyltransferase analysis found the OPPOSITE paralogue behaviour in the HBO1/MOZ modules - selectivity carried by one member while near-identical siblings ranked thousands of places away (JADE2 rank 38 against JADE3 11,635; ING5 148 against ING4 10,776). Paralogue pairs therefore cannot be assumed either redundant or divergent, and an HDAC1 claim built on analogy to KAT paralogue behaviour would be wrong in either direction. Oncofusion Knowledge Graph et al. 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Vorinostat, romidepsin, belinostat and panobinostat are FDA-approved for haematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3 and 6.

    Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. · Matthews GM, Mehdipour P, Cluse LA, Falkenberg KJ, Wang E, Roth M, et al. · Blood 126(21):2392-2403 2015
    PMID 26447190DOI
    What this evidence cannot show

    Taken from the introduction of a primary paper rather than from labels or a pharmacology review; cited only for the uncontroversial multi-isoform fact and not for potency ranking or regulatory status, which have changed since 2015.

    Evidence that argues against this (1)
    • The cited work exists to show that pharmacological breadth and genetic specificity give different answers, so it cannot be used to attribute an approved drug's activity to HDAC1. Its own design - combining genetic and pharmacological approaches across three malignancy models - is the argument against reading a pan-inhibitor result as an HDAC1 result. Matthews GM et al. 2015
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    A combined inhibition of HDAC1-3 induces ALOX5 promoter activity in an MLL-dependent manner, and constitutive activation of ALOX5 by MLL-AF4 was inhibited by class I HDAC inhibitors by relieving inhibitory functions deriving from MLL.

    Inhibition of class I HDACs abrogates the dominant effect of MLL-AF4 by activation of wild-type MLL. · Ahmad K, Katryniok C, Scholz B, Merkens J, Loscher D, Marschalek R, et al. · Oncogenesis 3(11):e127 2014
    PMID 25402609DOI
    What this evidence cannot show

    HDAC1, HDAC2 and HDAC3 were knocked down in combination, so the experiment attributes to the class and not to HDAC1. The readout is a single target gene, ALOX5, in promoter-reporter and knockdown experiments, not a leukaemia phenotype. Trichostatin A, a pan-HDAC inhibitor, is the primary chemical tool. Abstract read; PMCID PMC4259963, full text not fetched.

    Evidence that argues against this (1)
    • An MLL-dependent promoter response to combined HDAC1-3 inhibition does not separate the three enzymes, and the readout is ALOX5 promoter activity rather than leukaemic growth. This graph has recorded that the infant evidence in this beat sits with the class IIA erasers rather than the class I enzymes, and the direct t(4;11) result runs the other way entirely, proposing HDAC7 induction. de Barrios O et al. 2025
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Human HDAC1 is UniProt Q13547, primary gene name HDAC1, 482 amino acids, primary protein name 'Histone deacetylase 1'.

    UniProtKB Q13547 (HDAC1_HUMAN), Histone deacetylase 1 · UniProt Consortium · UniProtKB, retrieved 2026-09-20 2026
    What this evidence cannot show

    Resolved per rule 62: gene_exact:HDAC1 AND organism_id:9606 AND reviewed:true returned exactly one reviewed row and the PRIMARY gene name was read back as HDAC1. HDAC2 (Q92769, 488 aa) is a distinct record with no symbol collision, which was confirmed rather than assumed because the HDAC7 query in this same beat returned the HDAC9 record first.

    Evidence that argues against this (1)
    • A reviewed database record fixes the canonical sequence on the date it was read and nothing more. It does not establish which isoform is expressed in KMT2A-rearranged blasts, and this beat's own findings turn on distinctions a canonical record hides - HDAC9's catalytically inactive MITR form, and the nomenclature collision in which HDAC9's protein name reads 'Histone deacetylase 7B'. Accession and length are asserted here so a swap fails the validator, not because they carry biological weight. Vega-Garcia N et al. 2018
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