ASF1A - the compensating paralogue: the only gene in this beat that is not required in a single one of 1,208 cell lines, and it still has a leukaemia phenotype
also called ASF1A · anti-silencing function 1A · histone chaperone ASF1A · Q9Y294
ASF1A hands newly made histones to the machines that install them, and it is the back-up for a near-identical partner protein. Deleting it alone does nothing to any cancer cell line ever tested - which is exactly what a back-up looks like.
The same thing, for a scientist
ASF1A (Q9Y294, 204 aa) is the ASF1 paralogue that sits in the HIRA/HUCA complex [E1] and feeds the replication-independent H3.3 route. In mouse fetal liver haematopoiesis it is explicitly the **compensatory** partner, with ASF1B dominant [E2]. **Its DepMap profile is the most extreme negative in this beat and deserves to be stated as a positive finding about redundancy:** index mean **+0.009**, other-leukaemia mean -0.099, pan-essentiality **-0.187** across 1,208 lines [E3]. A gene effect above zero in the index arm means single knockout is, on average, not deleterious at all. Of the 29 genes in this beat's scan, ASF1A ranks second-least required in KMT2A-rearranged lines relative to comparators. And yet ASF1A has a published leukaemia phenotype: it accelerates chronic myeloid leukaemia blast crisis by activating Notch signalling [E4], and the TLK-ASF1 pathway is overexpressed across AML subtypes with ASF1 depletion reducing leukaemic growth [E5]. **The gap between 'does nothing in any screen' and 'accelerates blast crisis' is the most instructive thing about this gene** and is the same gap as CHAF1B's: screens measure complete loss in a proliferating line, and these phenotypes are about overexpression and context.
Overexpression phenotypes and knockout phenotypes are different experiments
Three of the four chaperones in this beat with real leukaemia literature have gain-of-function phenotypes:
| gene | published leukaemia phenotype | direction |
|---|---|---|
| CHAF1B | overexpression promotes leukaemia; heterozygous deletion suppresses it | gain |
| ASF1B | overexpression accelerates progression; deletion delays it | gain |
| ASF1A | overexpression accelerates CML blast crisis via Notch | gain |
| HIRA | over-expressed in CML samples; knockdown compacts chromatin and reduces BCR::ABL1 | gain |
Every one of them is a gene that leukaemia has too much of. That is a coherent pattern across four genes and three laboratories, and it is invisible to a loss-of-function screen by construction. It also changes what a therapeutic hypothesis in this layer should look like: the proposition is not 'inhibit an essential chaperone' but 'restore a normal amount of an over-supplied one', which is a much less familiar pharmacology and has no obvious modality.
The honest counter-reading is publication bias: overexpression is easy to do and easy to publish, and no paper reports a chaperone whose overexpression did nothing. This beat found no systematic survey of chaperone expression in leukaemia that would settle it.
| uniprot | Q9Y294 |
|---|---|
| gene symbol | ASF1A |
| length AA | 204 |
| paralogue | gene-asf1b |
| complex | protein-huca-complex |
| kmt2a literature records | 0 |
| paralogue hazard | ASF1A and ASF1B differ by 2 residues in length (204 vs 202); a length check cannot distinguish them |
depmap — the numbers behind the chart
{
"index_mean": 0.0093,
"other_leukaemia_mean": -0.099,
"difference": 0.1083,
"pan_essentiality": -0.1874,
"myeloid_difference": 0.1672,
"lymphoid_difference": 0.018,
"n_index": 11
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": 0.0093,
"chronos_mean_other_leukaemia": -0.099,
"difference": 0.1083,
"pan_essentiality_all_lines": -0.1874,
"selectivity_rank": 17044,
"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."
}- ASF1A and ASF1B cover for each other, so any single-paralogue intervention carries its own resistance mechanism and requires no mutation to fail.
- Depleting ASF1 rapidly induces alternative lengthening of telomeres, which would supply surviving cells with a telomere-maintenance mechanism - an intervention that could select for a more durable clone.
- The AML dependency is driven by marrow IL-1 beta, so the target's importance falls as inflammation falls and the drug would be least effective in exactly the low-burden state where minimal residual disease lives.
- Is the ASF1A/ASF1B pair genuinely redundant in a KMT2A-rearranged blast? The double knockout has not been run and this graph's expression control has not been applied to the pair in these lines.
- Four chaperones in this beat have gain-of-function leukaemia phenotypes and none has a loss-of-function dependency. Is that a real property of this layer or publication bias? A systematic survey of chaperone expression in paediatric leukaemia would settle it and does not exist.
- Do ASF1 levels change under menin or DOT1L inhibition? If the chaperone layer is over-supplied in leukaemia, its normalisation could be part of a drug's mechanism, and nobody has looked.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
ASF1a is a member of the quaternary HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone complex, assembled from recombinant proteins with HIRA as scaffold, and is involved with the other subunits in heterochromatinisation of the genome of senescent human cells.
Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex. · Rai TS, Puri A, McBryan T, et al. · Molecular and Cellular Biology 2011What this evidence cannot show
Abstract read from efetch 2026-09-20; full text not read. Human fibroblasts and recombinant reconstitution; no haematopoietic cell. Complex membership is established; a specific biochemical step within deposition is not assigned to ASF1a here.
Evidence that argues against this (1)
- ASF1 is not exclusive to the H3.3 route - it feeds CAF-1 and the replication-coupled pathway as well, and newer network interactomics adds an ASF1-SPT2 co-chaperone complex. Treating ASF1A as 'the HIRA-complex ASF1' understates how many routes it serves. Carraro M et al. 2023
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mouse fetal liver haematopoiesis ASF1B predominantly regulates H3.3-encoding genes and erythroid genes while ASF1A serves a compensatory function, and HIRA is dispensable in that compartment.
ASF1B promotes erythropoiesis by regulating the establishment and enrichment of H3.3 nucleosomes. · Liu J, Song X, Zhou L, et al. · Nucleic Acids Research 2026What this evidence cannot show
Abstract read from efetch 2026-09-20; full text not read. Mouse fetal liver erythroid development, not leukaemia and not human. 'Compensatory function' is the paper's word and the abstract does not describe the experiment that established it, so the strength of the compensation - partial or complete - is unverified here.
Evidence that argues against this (1)
- Compensation demonstrated in normal mouse erythropoiesis need not hold in a leukaemic blast with a different transcriptional programme and a different cell cycle. This graph's paralogue rule requires the silent paralogue to be shown expressed in the cells the claim is about, and that has not been done in any KMT2A-rearranged line. Oncofusion knowledge graph (internal analysis) 2026
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
In DepMap CRISPR gene effect, ASF1A's mean effect is +0.009 in 11 KMT2A-rearranged leukaemia lines against -0.099 in 43 other leukaemia lines (difference +0.108) at a pan-essentiality of -0.187 across 1,208 lines; in the myeloid half of the index arm the difference is +0.167 and in the lymphoid half +0.018.
Is any histone chaperone or variant-exchange gene selectively required in KMT2A-rearranged leukaemia lines, and does the answer survive a lineage split? · Oncofusion knowledge graph (internal analysis) 2026What this evidence cannot show
Run 2026-09-20. **A negative result reported as a negative result.** A positive mean gene effect in the index arm is within noise of zero and should not be read as a growth advantage on knockout. A single-gene screen cannot see a dependency covered by ASF1B, and the double knockout has not been run in any leukaemia line.
Evidence that argues against this (1)
- A published study reports that ASF1A overexpression accelerates CML blast crisis, and another that ASF1 depletion reduces leukaemic growth. The screen's silence is about complete single-gene loss in a proliferating culture, not about the protein's contribution. Yin X et al. 2022
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The histone chaperone ASF1A accelerates chronic myeloid leukaemia blast crisis by activating Notch signalling.
Histone chaperone ASF1A accelerates chronic myeloid leukemia blast crisis by activating Notch signaling. · Yin X, Zhou M, Zhang L, et al. · Cell Death & Disease 2022What this evidence cannot show
Record fetched from efetch 2026-09-20 for title, authors and DOI; the abstract was read from the search listing and the full text was not read (PMC9527247 exists). **CML blast crisis, a BCR::ABL1 disease, not a KMT2A fusion.** Graded moderate because this entry has not read the paper's experiments and the claim is being carried on its title and abstract. Cited for the direction of the phenotype - gain of function - rather than for the Notch mechanism, which this entry does not assess.
Evidence that argues against this (1)
- A gain-of-function phenotype in an over-expression system is the easiest chaperone result to obtain and the hardest to interpret, because abundant acidic histone-binding proteins perturb many processes when raised. No paper reports a chaperone whose overexpression did nothing, so the class of result is subject to publication bias that this beat found no way to bound. Yin J et al. 2026
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
ASF1A, ASF1B and the Tousled-like kinases are overexpressed in multiple genetic subtypes of AML, depletion of ASF1s significantly reduces leukaemic cell growth in vitro and in vivo in human models, and the pathway is driven by IL-1 beta from the microenvironment.
The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1beta-mediated AML progression. · Lin HY, Mohammadhosseini M, McClatchy J, et al. · Blood 2024What this evidence cannot show
Abstract read from efetch 2026-09-20; full text not read (PMC11340594 exists). AML across genetic subtypes with no KMT2A-rearranged arm named in the abstract; the index disease here is infant B-ALL. 'Depletion of ASF1s' is plural in the abstract, so the paralogue-specific contribution is not resolved from it. The Greek letter in the title is rendered as 'beta' because this project has documented that the tool chain drops italicised and special characters silently; identifiers were copied from the same fetched record.
Evidence that argues against this (1)
- DepMap finds neither ASF1 paralogue required in any of 1,208 lines. If the dependency requires an IL-1 beta signal supplied by the marrow, then it is invisible to in-vitro screens and also to any therapeutic model that does not reproduce the niche - which is most of them. Oncofusion knowledge graph (internal analysis) 2026
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
ASF1A is UniProt Q9Y294 (ASF1A_HUMAN), histone chaperone ASF1A / anti-silencing function protein 1 homolog A, 204 amino acids, with no alias gene symbols in the reviewed record; ASF1B is a separate reviewed record Q9NVP2 of 202 amino acids.
UniProtKB Q9Y294 (ASF1A_HUMAN), Histone chaperone ASF1A, 204 aa · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026What this evidence cannot show
Fetched 2026-09-20 with `gene_primary` requested and read back per rule 62; exactly one reviewed human record per symbol and neither lists the other as an alias. **The two paralogues differ by two residues in length, so this project's length check cannot catch a swap between them.** The accession is asserted for that reason.
Evidence that argues against this (1)
- This is the hardest case in the project for rule 63: same family, same function, near-identical length, and the literature frequently writes 'ASF1' without a suffix. Any claim attributed to one paralogue from a paper that wrote 'ASF1s' is naming and not measurement. UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
upstream H3-H4 donor subunit of HUCA
paralogue pair; ASF1A compensates for ASF1B in fetal liver haematopoiesis
sNASP-H3-H4-ASF1b co-chaperone complex places NASP upstream of ASF1
HUCA component in the replication-independent deposition route