ELOVL1 - the fatty-acid elongase that infant MLL-AF4 ALL retains from its fetal origin, and the lipid enzyme on the opposite side of the divide from ACSL4
also called ELOVL1 · SSC1 · very long chain fatty acid elongase 1 · 3-keto acyl-CoA synthase ELOVL1 · Q9BW60
ELOVL1 lengthens saturated fats into very long ones, and it is one of the genes infant MLL-AF4 leukaemia keeps switched on from its origin before birth. Switching it off kills those leukaemia cells, which makes altered fat handling a feature of the infant disease rather than an afterthought.
The same thing, for a scientist
ELOVL1 (UniProt Q9BW60, 279 aa, primary gene name read back 2026-09-20) catalyses the condensing step of very-long-chain fatty acid elongation, with a substrate preference for saturated and monounsaturated C20-C26 acyl-CoAs. It reaches this graph through an unusual route: not a dependency screen, but a **developmental** one. Symeonidou et al. defined a conserved fetal transcriptional signature across human and mouse fetal, neonatal and adult haematopoietic stem and progenitor cells, found that this signature persists in infant ALL blasts, and from within it identified genes critical for survival of MLL-AF4-positive ALL cells - of which the two singled out were PLK1 and **ELOVL1**, the latter highlighting altered fatty acid metabolism as a feature of infant ALL [E1]. The entry matters because it is one of very few metabolic findings in this beat obtained in the **lymphoid, infant, KMT2A::AFF1** disease, and because it sits on the opposite side of the saturation divide from the myeloid lipid dependency ACSL4 [E2]. Same founding lesion, two lineages, two incompatible lipid requirements - which is the cleanest evidence in this beat that the metabolic phenotype is not a single property of the fusion.
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.
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.
A fetal-origin finding, not a metabolic-screen finding
The provenance changes what the result means. ELOVL1 was not found by asking 'which metabolic gene is this leukaemia addicted to'. It was found by asking 'which parts of the fetal programme does this leukaemia still have', and then testing that list functionally 1. So the honest reading is: infant MLL-AF4 ALL retains a fetal lipid-elongation programme and needs it. That is a statement about ontogeny first and metabolism second.
It also means the comparator built into the discovery is a developmental stage, not a fusion-negative leukaemia. The paper does not claim ELOVL1 is a KMT2A-selective dependency against other B-ALL subtypes; it claims it is critical for survival of MLL-AF4-positive ALL cells within a fetal-signature framework 1. This graph should carry the weaker, accurate claim.
ELOVL1 against ACSL4: the split that should stop a class-level lipid strategy
| myeloid KMT2A-r AML | infant KMT2A::AFF1 ALL | |
|---|---|---|
| enzyme | ACSL4 2 | ELOVL1 1 |
| substrate class | long-chain polyunsaturated | saturated / monounsaturated very-long-chain |
| discovery route | CRISPR-Cas9 dependency screen | conserved fetal transcriptional signature |
| validation | CRISPRi, shRNA, colony assays, in vivo MLL-AF9 | functional validation in MLL-AF4+ ALL cells |
These are not two views of one dependency. Supplying polyunsaturated fatty acids rescues the ACSL4 phenotype 2; nothing about that would rescue a very-long-chain saturated elongation defect. A 'lipid metabolism strategy for KMT2A-rearranged leukaemia' would therefore have to be two different strategies, and a trial enrolling both lineages on a single lipid rationale is a trial designed to fail in one arm.
The state-level version of this observation is in cell-state-lipid-pufa-dependence; this entry is the lymphoid enzyme itself.
| uniprot | Q9BW60 |
|---|---|
| length AA | 279 |
| alphafold ID | AF-Q9BW60-F1 |
| ec number | 2.3.1.199 |
| pathway | very-long-chain fatty acid elongation (condensing step); saturated and monounsaturated C20-C26 substrates |
| resolution note | gene_exact:ELOVL1 AND organism_id:9606 AND reviewed:true returned 1 reviewed row on 2026-09-20; gene_primary read back as ELOVL1; length 279 aa asserted. Family warning recorded: ELOVL2/ELOVL5 act on polyunsaturated substrates and a numeral confusion inverts the substrate-class argument. |
| evidence lineage | lymphoid, infant, MLL-AF4-positive ALL - one of the few metabolic findings in this beat in the index disease |
| discovery route | conserved human/mouse fetal HSPC transcriptional signature retained in infant ALL blasts, then functional validation |
| counterpart enzyme | ACSL4 in myeloid KMT2A-rearranged AML, acting on the opposite substrate class |
| direction in disease | pro-leukaemic; critical for survival of MLL-AF4-positive ALL cells |
| tool availability | no selective ELOVL1 inhibitor described in the cited work |
| subnuclear localization | NOT APPLICABLE. ELOVL1 is a seven-transmembrane integral ER membrane enzyme with no annotated nuclear pool in UniProt, no annotated NLS, and no reported nuclear localisation in any system. Recording this as NOT APPLICABLE rather than as an unmeasured gap deliberately keeps it OUT of the denominator of things nobody has looked at - the handling Q87 gave B2M (secreted) and PROM1 (five-transmembrane) in tranche 2. The outer nuclear membrane is continuous with the rough ER, so a perinuclear ER pool certainly exists; that is ER at the nuclear periphery, not a subnuclear compartment, and no ELOVL1 paper makes a subnuclear claim. |
| localization shown for fusion | NO - nobody has localised ELOVL1 in any KMT2A-rearranged cell, in any lineage. The functional requirement WAS shown in MLL-AF4 (KMT2A::AFF1) human infant ALL cells [E_q89_elovl1_loc3], so this is the unusual case where the fusion-specific FUNCTION is established while the fusion-specific COMPARTMENT was never a question, because topology settles it. |
depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.4604,
"chronos_mean_other_leukaemia": -0.2887,
"difference": -0.1717,
"pan_essentiality_all_lines": -0.2266,
"selectivity_rank": 349,
"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."
}localization
{
"subcellular": "ENDOPLASMIC RETICULUM MEMBRANE, multi-pass. UniProt Q9BW60 fetched 2026-09-21 carries exactly one SUBCELLULAR LOCATION value - 'Endoplasmic reticulum membrane', topology 'Multi-pass membrane protein' - supported by ECO:0000255 HAMAP-Rule MF_03201 AND by two experimental attributions, ECO:0000269 PubMed:20937905 and ECO:0000269 PubMed:30487246. The feature table carries SEVEN helical transmembrane segments: 23-43, 61-81, 110-130, 137-154, 176-196, 201-221, 231-251 [E_q89_elovl1_loc1].",
"why_the_compartment_is_the_mechanism": "ELOVL1 catalyses the condensing step of very-long-chain fatty-acid elongation, an ER-membrane process; Ohno et al. established its substrate specificity, showed it is required for C24 sphingolipid production and found its activity co-regulated with the ER ceramide synthase CERS2 [E_q89_elovl1_loc2]. The compartment is where the substrates and the partner enzyme are.",
"system_of_the_localisation_evidence": "Not haematopoietic and not fusion-bearing. Neither UniProt attribution is a leukaemia experiment."
}cell type
{
"answer": "MLL-AF4-POSITIVE (KMT2A::AFF1) INFANT B-ALL BLASTS, and by ontogeny the FETAL HAEMATOPOIETIC STEM AND PROGENITOR CELL. UniProt records the tissue distribution as 'Ubiquitous', so the useful cell-type statement is not where the enzyme exists but where it is REQUIRED. Symeonidou et al. defined a conserved fetal transcriptional signature across human and mouse fetal, neonatal and adult HSPCs, showed it persists in infant ALL blasts, and functionally validated ELOVL1 as critical for survival of MLL-AF4-positive ALL cells [E_q89_elovl1_loc3].",
"grade": "Functional requirement in the index fusion's own lineage and fusion - unusually good for this graph - but the protein was not localised in those cells."
}cell state
{
"state": "FETAL PROGRAM RETENTION. ELOVL1 reaches this graph inside a fetal signature that persists after birth in infant MLL-AF4 blasts; see cell-state-fetal-program-retention. The adjacent lipid state is cell-state-lipid-pufa-dependence, and ELOVL1 sits on the saturated/monounsaturated side of that divide while ACSL4 sits on the polyunsaturated side, a split this entry already records.",
"bounded": "No ELOVL1 cell-state measurement exists outside the Symeonidou fetal-signature framing."
}localization bounded absence
{
"date": "2026-09-21",
"tool": "NCBI esearch db=pubmed",
"query": "ELOVL1[tiab] AND (\"endoplasmic reticulum\"[tiab] OR localization[tiab] OR localisation[tiab])",
"querytranslation": "\"ELOVL1\"[Title/Abstract] AND (\"endoplasmic reticulum\"[Title/Abstract] OR \"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract])",
"count": 7,
"reading": "Seven records, none a leukaemia localisation study. The compartment question for this protein is closed by topology, not by literature volume.",
"absence_class": "never-measured (for the fusion-context question only; the wild-type compartment IS measured)"
}- Very-long-chain fatty acid elongation is essential in skin barrier, myelin and retina. ELOVL1 loss-of-function in humans causes a severe neuro-ichthyotic syndrome, so systemic ELOVL1 inhibition in an infant whose brain and skin are still developing is a serious essential-function risk, not a theoretical one.
- No selective inhibitor exists, so the route to testing this in an animal is genetic; a therapeutic proposal here is currently a chemistry programme, not a repurposing.
- The dependency was found inside a fetal programme that the leukaemia shares with normal fetal and neonatal progenitors. An agent that works by attacking a retained fetal programme is, by construction, an agent with a narrow window against the infant's own haematopoiesis.
- Compensation is likely: seven ELOVL enzymes with overlapping substrate ranges, and the ACSL4 study in the sibling lineage already documented compensatory activation of lipid pathways on loss of a single lipid enzyme.
- Is ELOVL1 a KMT2A::AFF1-selective dependency, or a fetal-programme dependency shared by any leukaemia of fetal origin? The published comparator is developmental stage, so the fusion-selectivity question has not been asked.
- What is the actual product that matters - a specific very-long-chain species, a sphingolipid, or membrane order? Without a lipidomic readout the mechanism is an enzyme name rather than a pathway.
- Does ELOVL1 loss phenocopy in vivo? The published validation is in cells; no xenograft result is claimed.
- Do myeloid KMT2A-rearranged cells need ELOVL1, and do infant KMT2A::AFF1 cells need ACSL4? Two knockdowns in each other's systems would convert a juxtaposition of two papers into a measured lineage interaction, and it is a week of work.
- ELOVL1 is required for survival of MLL-AF4 ALL cells and has never been imaged in one. Does the enzyme redistribute within the ER - for instance to ER-mitochondria contact sites - in fusion-bearing blasts, and would that change which lipid pools are accessible?
- Is the ELOVL1 requirement inherited from the fetal HSPC program or created by KMT2A::AFF1? A side-by-side dependency comparison in fetal HSPCs, adult HSPCs and MLL-AF4 blasts would settle it and has not been done.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Multiple RNA-sequencing experiments on fetal, neonatal and adult haematopoietic stem and progenitor cells from human and mouse defined a conserved fetal transcriptional signature, prominently proliferative and oncogenic, that persists in infant ALL blasts; from this signature, functional validation studies identified a number of genes critical for survival of MLL-AF4-positive ALL cells, of particular interest PLK1 and ELOVL1, the latter highlighting altered fatty acid metabolism as a feature of infant ALL.
Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements. · Symeonidou V, Jakobczyk H, Bashanfer S, ..., Ottersbach K · Cell Rep 2021What this evidence cannot show
Abstract read this session; full text not retrieved, so the identity of the MLL-AF4-positive cell models, the knockdown efficiency and the magnitude of the survival effect were not checked. **The comparator is developmental stage, not fusion status**, so this is not evidence that ELOVL1 is selective for KMT2A::AFF1 against other B-ALL subtypes; the abstract makes no such comparison. No in vivo ELOVL1 result is claimed in the abstract, and no ELOVL1 inhibitor is described. Bounded absence: a Europe PMC sweep on 2026-09-20 using the instrument in ana-metabolic-enzyme-enumeration-kmt2a-bounded-absences found no independent replication of the ELOVL1 requirement in this disease.
Evidence that argues against this (1)
- The myeloid form of the same founding lesion has a different and substrate-incompatible lipid dependency: ACSL4, a polyunsaturated-fatty-acid activating enzyme whose loss is rescued by exogenous PUFA supplementation. Any generalisation of ELOVL1 to KMT2A-rearranged disease as a class is contradicted by that result. Schafer S et al. 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
ACSL4 is a selective, functionally validated vulnerability in KMT2A-rearranged AML acting on polyunsaturated lipid species, with exogenous PUFA supplementation rescuing the ACSL4-loss growth defect - a substrate class distinct from, and not interchangeable with, the saturated and monounsaturated very-long-chain substrates of ELOVL1.
ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia. · Schafer S, Rahimian E, Schmitz-Hubsch L, ..., Wurm AA · Cell Rep 2026What this evidence cannot show
Abstract read this session. Cited here for the contrast, not as evidence about ELOVL1. Myeloid systems only. The substrate-class incompatibility argued in this entry is an inference from enzyme biochemistry rather than a head-to-head experiment: no study has tested ACSL4 in KMT2A::AFF1 lymphoid cells or ELOVL1 in MLL-AF9 myeloid cells, so the lineage split is a juxtaposition of two studies and not a measured interaction.
Evidence that argues against this (1)
- Because the two enzymes have never been tested in each other's systems, the clean lineage story could be an artefact of which screen was run where. The alternative reading - that both enzymes matter in both lineages and each study found the one its discovery route was capable of finding - is not excluded by anything published. Symeonidou V et al. 2021
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt reviewed human record Q9BW60 (ELOV1_HUMAN) has primary gene name ELOVL1, gene synonym SSC1, length 279 aa, EC 2.3.1.199, recommended protein name 'Very long chain fatty acid elongase 1'.
UniProtKB entry Q9BW60 (ELOV1_HUMAN), Very long chain fatty acid elongase 1 · UniProt Consortium · UniProt 2026What this evidence cannot show
Resolved 2026-09-20 with gene_exact:ELOVL1 AND organism_id:9606 AND reviewed:true; exactly one reviewed row and gene_primary read back as ELOVL1. The ELOVL family has seven human members with distinct substrate preferences, and the numerals are the only thing separating them in most prose - ELOVL1, ELOVL3 and ELOVL7 all act on saturated/monounsaturated very-long-chain substrates while ELOVL2 and ELOVL5 act on polyunsaturated ones, so an ELOVL1/ELOVL5 confusion would invert the entire argument of this entry. The synonym SSC1 is short and collides with unrelated genes in other organisms and should not be used as a literature-search key.
Evidence that argues against this (1)
- A reviewed record fixes the sequence and symbol on the date read. It cannot establish that ELOVL1 rather than a co-expressed family member carries the requirement in MLL-AF4 cells, and the cited study's abstract does not report a family-wide comparison. Symeonidou V et al. 2021
- E_q89_elovl1_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
ELOVL1 (Q9BW60, 279 aa, primary gene name ELOVL1 read back 2026-09-21) carries exactly one UniProt subcellular location, 'Endoplasmic reticulum membrane', multi-pass topology, with two experimental attributions (PubMed:20937905, PubMed:30487246) alongside HAMAP-Rule MF_03201, and seven annotated helical transmembrane segments spanning residues 23-251. There is no nuclear location value and no annotated nuclear localisation signal.
UniProtKB Q9BW60 (ELOV1_HUMAN) SUBCELLULAR LOCATION comment and feature table, fetched 2026-09-21 · UniProt Consortium · UniProtKB 2026What this evidence cannot show
A UniProt location comment is a curated statement, and rule 91 warns that even an ECO:0000269 attribution may point at a paper that is not about localisation. Here the HAMAP family rule and the seven transmembrane features are independent structural support for the same call, which is why this is graded established. The subnuclear NOT APPLICABLE verdict rests on absence of a nuclear annotation, which is weaker than a positive exclusion experiment, and the entry says so rather than implying an exclusion was performed.
Evidence that argues against this (1)
- The strongest counter-argument is that ABSENCE OF A NUCLEAR ANNOTATION IS NOT AN EXCLUSION EXPERIMENT, and multi-pass ER proteins are not automatically disqualified from a nuclear-envelope pool: the outer nuclear membrane is continuous with the rough ER, so an ER-resident enzyme sits at the nuclear periphery throughout interphase. What defeats the objection for the SUBNUCLEAR question specifically is that the nuclear envelope is not one of the compartments this dimension asks about (nucleolus, speckles, PML bodies, chromatin), and a seven-pass integral membrane protein cannot be soluble in nucleoplasm. The bound actually run is in data.localization_bounded_absence: seven records, zero making any nuclear claim. UniProt Consortium 2026
- E_q89_elovl1_loc2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
ELOVL1's compartment is functionally coupled to its chemistry: it shows high in-vitro activity toward saturated and monounsaturated C20- and C22-CoAs, is essential for production of C24 sphingolipids, and its activity is co-regulated with the ER ceramide synthase CERS2. Knockdown of ELOVL1 reduced activity of the Src-family kinase LYN, which the authors read as C24 sphingolipids mattering for membrane microdomain function.
ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. · Ohno Y, Suto S, Yamanaka M, Mizutani Y, Mitsutake S, Igarashi Y, Sassa T, Kihara A · Proc Natl Acad Sci U S A 2010What this evidence cannot show
In-vitro enzymology plus knockdown in non-haematopoietic cells; abstract read, full text not read. This is one of the two papers UniProt cites for the ER-membrane call.
Evidence that argues against this (1)
- This citation should NOT be read as a localisation experiment, and saying so argues against the entry's own use of it. The abstract describes substrate specificity, sphingolipid output and a kinase readout; it describes no immunofluorescence and no fractionation placing ELOVL1 in the ER. So one of UniProt's two experimental attributions for the ER call is, at abstract level, functional rather than positional - the same defect rule 91 documents for MEN1, KMT2A, AFF1 and AFF4. The ER call survives on the HAMAP rule and the transmembrane topology; a reader wanting a primary imaging citation for human ELOVL1 will not find one in this entry, and this beat did not find one in the seven-record bounded query either. UniProt Consortium 2026
- E_q89_elovl1_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In HUMAN infant MLL-AF4 (KMT2A::AFF1) acute lymphoblastic leukaemia cells, ELOVL1 is a functionally validated survival requirement identified from a conserved fetal transcriptional signature defined across human and mouse fetal, neonatal and adult haematopoietic stem and progenitor cells and shown to persist in infant ALL blasts. PLK1 was the other gene singled out.
Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements. · Symeonidou V, Jakobczyk H, Bashanfer S, Malouf C, Fotopoulou F, Kotecha RS, Anderson RA, Finch AJ, Ottersbach K · Cell Rep 2021What this evidence cannot show
The fusion is MLL-AF4, i.e. the index fusion KMT2A::AFF1 - stated explicitly because naming the wrong fusion has been a real error in this project. This establishes a CELL TYPE in which ELOVL1 is required; it does NOT establish where in that cell the protein sits, which was never imaged. Abstract read; the functional-validation panel and the identity of the ALL lines were not read from full text. This paper is already cited in this entry as E1 and the identifiers here were re-fetched from PubMed rather than copied from the sibling block, as the brief requires.
Evidence that argues against this (1)
- A fetal-signature-derived requirement is not a fusion-specific one, and the entry should resist that slide. The signature is defined by ONTOGENY - fetal versus adult HSPCs - not by fusion status, so the most economical reading is that ELOVL1 is a fetal-HSPC dependency that infant MLL-AF4 blasts inherit along with the rest of the fetal program rather than something the fusion creates. That distinction is therapeutically decisive: on the inherited reading, normal fetal and neonatal progenitors share the vulnerability, which is the worst possible toxicity profile for a disease of infants. Nothing in the abstract resolves which reading is right, and no adult-leukaemia-versus-infant comparison of ELOVL1 dependency is reported. Symeonidou V et al. 2021
opposite side of the saturated/polyunsaturated divide; the lineage split in lipid dependency
the lymphoid enzyme inside the lipid-dependent state entry
- depends on →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
critical for survival of MLL-AF4-positive ALL cells within the retained fetal signature
retained from the conserved fetal HSPC programme that persists in infant ALL blasts
identified from within the conserved fetal transcriptional signature
a fetal-programme metabolic requirement in the infant lymphoid disease
ELOVL1 is one of two genes functionally validated out of the conserved fetal HSPC signature that persists in infant MLL-AF4 blasts (PMID 34706236); that cell state is why the gene is in this graph (Q89 2026-09-21)
ELOVL1 sits on the saturated/monounsaturated VLCFA side of the lipid divide, ACSL4 on the polyunsaturated side; subnuclear localisation for ELOVL1 is NOT APPLICABLE - a seven-pass ER membrane enzyme (Q89 2026-09-21)