ACIN1 (Acinus) - a splicing/apoptosis protein whose only domain is the 35-residue module the leukaemic fusion keeps, and whose entire localization record is uncoded

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.

• Targeting ACIN1 to treat an ACIN1::NUTM1 leukaemia would be aimed at the wrong molecule: the fusion keeps 106 of 1,341 residues, so an inhibitor of ACIN1's splicing or apoptotic functions would act only on the wild-type allele - in a cell that still needs it - and leave the oncoprotein untouched.
• SRPK2 is the one druggable node adjacent to this protein, and its published effect is to INCREASE leukaemia proliferation through cyclin A1, which makes SRPK2 inhibition superficially attractive. But that axis requires Ser-1180, which the fusion does not have, so the rationale applies to wild-type acinus in myeloid disease and not to the B-ALL fusion.
• ACIN1 suppresses the pro-apoptotic Bcl-X(S) isoform. Any agent that restores or enhances ACIN1 function in a NUTM1-fusion blast would be expected to make it LESS apoptosis-prone, i.e. to work against the chemosensitivity that currently cures these children.
• This protein's name will keep causing category errors. Any name-based or text-mined instrument scanning for epigenetic regulators will score 'apoptotic chromatin condensation inducer' as a chromatin modifier; it is not one, and the entry says so explicitly with the fetched domain architecture behind it.

1. What does the SAP domain actually bind? SAP is a scaffold-attachment-factor-family module, which predicts AT-rich or matrix-associated DNA rather than promoter-selective binding. If that is right, the ACIN1::NUTM1 oncoprotein's address is a very different kind of address from KMT2A's CpG-selective CXXC, and its HOXA9 activation would need a different explanation than direct promoter binding.
2. Do the Ser-1180 and S422 numberings refer to one residue? An alignment of the UniProt canonical against the isoform used in PMID 18559500 would settle it in minutes and would close a discrepancy that currently reads as two separate phosphosites in two separate places.
3. Is the remaining wild-type ACIN1 allele haploinsufficient in an ACIN1::NUTM1 blast? ACIN1's normal job includes suppressing formation of the pro-apoptotic Bcl-X(S) isoform. If one allele is not enough, the leukaemic cell would sit closer to the apoptotic threshold - which is a concrete candidate explanation for this subtype's chemosensitivity and is testable by Bcl-X isoform ratios in KOPN32 against an ACIN1-wild-type B-ALL line.
4. Is the SRPK2-acinus-cyclin A1 axis active in B-lineage as well as myeloid leukaemia? The published axis is AML and the NUTM1 fusion disease is B-ALL, so the two ACIN1-leukaemia connections currently sit in different lineages and nobody has asked whether they meet.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProtKB Q9UKV3 (ACINU_HUMAN) is 1341 aa with exactly one annotated domain, SAP at aa 72-106 (Pfam PF02037), six predicted disordered regions, and a region at 1210-1237 sufficient for RNPS1/SAP18 binding and ASAP-complex formation; its Pfam complement is PF02037 (SAP), PF16294 (RSB_motif) and PF28976 (RRM_ACIN1); FUNCTION carries five ECO:0000269 citations and describes exon junction complex and ASAP complex membership, RNA binding, inhibition of pro-apoptotic Bcl-X(S) formation, caspase-3-activated apoptotic chromatin condensation and regulation of cyclin A1 but not A2 in leukaemia cells; and all four localization statements - Nucleus, Nucleus speckle, Nucleus nucleoplasm, and the note that Ser-1180 phosphorylation by SRPK2 moves it from speckles to nucleoplasm - carry NO evidence code, as does the TISSUE SPECIFICITY statement that the Ser-1180-phosphorylated form is highly expressed and phosphorylated in patients with myeloid haematologic malignancies.

   UniProtKB Q9UKV3 (ACINU_HUMAN) - Apoptotic chromatin condensation inducer in the nucleus, Homo sapiens · UniProtKB 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-22 by gene_exact:ACIN1 AND organism_id:9606 AND reviewed:true (one reviewed hit; accession and length read back from the returned record), then re-fetched by accession for the 35-item reference list. HGNC:17066 and location 14q11.2 fetched separately from rest.genenames.org, which also gives ACINUS as the previous symbol and KIAA0670 and fSAP152 as aliases. The absence of evidence codes on the localization comments is a property of the record as served on that date; it does NOT mean no experiment exists - the experiment does exist and is [E3] - only that the annotation is not coded to it. The disordered regions are ECO:0000256 predictions.

   ▸Evidence that argues against this (1)

   • The uncoded lines are where the most useful statements sit in this record - the speckle-to-nucleoplasm switch and the myeloid-malignancy observation are both uncoded, while the well-coded FUNCTION field says nothing about either. An ECO:0000269 filter applied to this entry would keep the least surprising content and discard the rest. Jang SW et al. 2008
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Acinus is a nuclear factor that induces apoptotic chromatin condensation after cleavage by caspase-3, without inducing DNA fragmentation; immunodepletion showed it to be essential for apoptotic chromatin condensation in vitro and an antisense study showed it to be important for the same process in cells.

   Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation · Sahara S, Aoto M, Eguchi Y, et al. · Nature 1999
   PMID 10490026DOI
   ▸What this evidence cannot show

   A 1999 in-vitro reconstitution plus antisense knockdown, i.e. pre-RNAi methodology, and the naming paper for the protein. This activity requires caspase-3 cleavage of the full-length protein and is therefore NOT available to the ACIN1::NUTM1 fusion, which retains only aa 1-~106 of ACIN1 [E4]. It is cited here to establish what the protein is named for and to keep 'condenses chromatin' separate from 'modifies or reads a chromatin mark'.

   ▸Evidence that argues against this (1)

   • Acinus-mediated DNA fragmentation is itself regulated by an antiapoptotic partner, AAC-11, so the apoptotic activity is not a simple switch and the protein's net effect on cell death depends on its complex context - which is also why the ASAP complex disassembles after apoptosis is induced. EMBO Journal 2009
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   SRPK2 binds and phosphorylates acinus and redistributes it from the nuclear speckles to the nucleoplasm, upregulating cyclin A1 but not cyclin A2; the phosphomimetic acinus S422D enhances cyclin A1 transcription while the unphosphorylatable S422A blocks SRPK2's stimulatory effect; ablation of acinus or SRPK2 abolishes cyclin A1 expression in leukaemia cells and arrests them in G1, overexpression of either increases leukaemia cell proliferation, and both are overexpressed in some human acute myelogenous leukaemia patients with correlated cyclin A1 levels.

   Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1 · Jang SW, Yang SJ, Ehlen A, et al. · Cancer Research 2008
   PMID 18559500DOI
   ▸What this evidence cannot show

   THE RESIDUE NUMBER DOES NOT MATCH THE DATABASE. This paper mutates S422; UniProt's note for the same mechanism says Ser-1180. ACIN1 has short and long isoforms and the two numbers are presumably one residue in two frames, but THIS ENTRY HAS NOT VERIFIED THE ALIGNMENT and does not assert it. Cell lines plus patient-sample correlation; the AML association is correlative and the disease is MYELOID, whereas the NUTM1 fusion disease is B-lymphoid, so this is a separate ACIN1-leukaemia link and not background for the fusion. The phosphosite is C-terminal and is NOT retained in ACIN1::NUTM1.

   ▸Evidence that argues against this (1)

   • This mechanism is unavailable to the fusion oncoprotein: the retained ACIN1 fragment ends around residue 106, roughly 1,074 residues N-terminal of Ser-1180, so neither the speckle residence nor its phospho-regulation can be inherited by ACIN1::NUTM1 - which is exactly why the fusion's subnuclear address must be measured rather than inferred from this protein. Pincez T et al. 2020
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   ACIN1 is the commonest NUTM1 fusion partner in infant B-ALL (17 of 39 infant cases with a known partner, 44%), and the fusion joins ACIN1 exon 3 or exon 4 to NUTM1 exon 3, retaining the functional DNA-binding SAP domain of ACIN1 and most of NUTM1; the rearrangement is cryptic and undetectable by standard cytogenetics.

   Cryptic recurrent ACIN1-NUTM1 fusions in non-KMT2A-rearranged infant acute lymphoblastic leukemia · Pincez T, Landry JR, Roussy M, et al. · Genes, Chromosomes and Cancer 2020
   PMID 31515871DOI
   ▸What this evidence cannot show

   The breakpoint and SAP-retention statements are from this two-patient founding report; the 44% frequency is from the separate 85-case Ponte di Legno/Interfant series (PMID 34211097, read in full from PMC8478641) and is combined here into one claim, which is why both sources are named. Neither source gives residue boundaries for the retained ACIN1 fragment - the aa 72-106 SAP coordinates come from live UniProt [E1] and the inference that everything C-terminal is lost follows from the domain's N-terminal position.

   ▸Evidence that argues against this (1)

   • A 175-infant single-centre series instead reports BRD9::NUTM1 as the commonest NUTM1 fusion in its KMT2A-wild-type group. That group is n=9, so this is very probably sampling, but the published record disagrees with itself and both figures should be carried. Ilyasova K et al. 2025
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The ASAP complex is composed of SAP18, RNPS1 and Acinus isoforms, inhibits RNA processing in vitro, accelerates cell death when microinjected into mammalian cells, and disassembles after apoptosis is induced, linking RNA processing to apoptosis.

   ASAP, a novel protein complex involved in RNA processing and apoptosis · Schwerk C, Prasad J, Degenhardt K, et al. · Molecular and Cellular Biology 2003
   PMID 12665594DOI
   ▸What this evidence cannot show

   HeLa extracts and in-vitro splicing reactions plus microinjection; no haematopoietic system. Complex membership is mediated by ACIN1 sequence C-terminal of residue 1200 and is therefore not available to the ACIN1::NUTM1 fusion.

   ▸Evidence that argues against this (1)

   • A later structural study of the ASAP core reports a related Pinin-containing PSAP complex, so the SAP18/RNPS1 scaffold is shared with a paralogous complex that does not contain Acinus - meaning ASAP-attributed activities are not uniquely ACIN1's. Nature Structural & Molecular Biology 2012

• ← part ofACIN1::NUTM1 - the commonest NUTM1 fusion in infants, cryptic to cytogenetics, and the only one with a human cell line

  5' partner, exon 3 or exon 4 - retains ONLY the SAP DNA-binding domain (aa 72-106, PF02037) and loses every documented ACIN1 activity, all of which maps C-terminal of residue 1000

• fuses with →NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis

  ACIN1::NUTM1 - the modal NUTM1 partner in infant B-ALL (44%)