SPRED1 - the RAS/MAPK brake whose deletion marks relapse in paediatric B-ALL, third-widest margin in the Q152 AFF1-only core
also called Spred-1 · hSpred1 · Sprouty-related EVH1 domain-containing protein 1
SPRED1 is a brake on the RAS growth-signalling pathway. Children whose leukaemia has lost SPRED1 relapse more often. Its switch is occupied in three of the eight KMT2A::AFF1 samples here and in none of the others, with one of the cleanest separations in the set.
The same thing, for a scientist
SPRED1 (Q7Z699, 444 aa) is a Sprouty-related EVH1-domain protein that inhibits RAS/MAPK signalling; germline loss causes Legius syndrome. In a population-based series of 307 uniformly treated paediatric ALL cases, SPRED1 deletion was significantly more common in patients who relapsed or had induction failure and was associated with decreased 10-year event-free survival and with poorer overall survival in univariate analysis - in the same analysis in which MLL rearrangements were also associated with decreased event-free survival. Its promoter is occupied in 3 of 8 KMT2A::AFF1 samples of GSE252378 (TB986292, p279, p454) at 2.03-4.54x with the highest non-AFF1 value 1.28x and no non-AFF1 sample above 1.5x - a margin of 1.59, third widest in the 17-gene core.
The interesting collision with EPHA7
EPHA7, the one core member with published KMT2A::AFF1 promoter occupancy, acts through ERK phosphorylation [see gene-epha7]. SPRED1 is a negative regulator of the same pathway. Both are in this 17-gene core and both have wide separation margins (1.84 and 1.59). This beat does not have the power to say whether that is a MAPK-axis signal or a coincidence in a set of seventeen - the pre-registered enrichment test was underpowered and no MAPK gene set was pre-specified, so testing one now would be a post-hoc choice. It is recorded here as a pre-registration for a later cycle, not as a finding.
| uniprot | Q7Z699 |
|---|---|
| length AA | 444 |
| gene symbol | SPRED1 |
| hgnc symbol | SPRED1 |
| chromosome | 15q14 |
| promoter hg38 | chr15:38,251,835-38,253,835 (TSS 38,252,835, plus strand, NM_152594) |
| shown for fusion | NO - nobody has published a KMT2A-fusion occupancy or knockdown experiment on SPRED1 that this beat could find. |
| relationship to existing entries | Named by beat Q152 because its promoter sits in the 17-gene AFF1-only recurrent core of GSE252378. Q152's headline result is that that core is NOT more recurrence than a label permutation gives (p = 0.11). This entry therefore does NOT claim the gene is a KMT2A::AFF1 target; it exists because the gene is real biology in this disease and had no entry. |
measurements
[
{
"quantity": "n_aff1_samples_occupied",
"subject": "SPRED1 2 kb promoter in the KMT2A::AFF1 arm of GSE252378",
"value": 3,
"units": "samples of 8",
"n": 27,
"universe": "27 GSE252378 KMT2A-fusion samples, two-antibody 2.0x plus per-library width-matched floor",
"null": 2.73,
"note": "TB986292, p279, p454; occupied calls 2.03-4.54x; 0 of 19 non-AFF1, highest non-AFF1 1.28x (A89691), margin 1.59"
}
]- SPRED1 loss activates RAS/MAPK, and RAS-pathway mutation is already recorded in this graph as a menin-inhibitor resistance route; a SPRED1-deleted KMT2A::AFF1 blast would be predicted to resist menin inhibition for reasons that have nothing to do with the menin interface.
- Are any of the GSE252378 KMT2A::AFF1 samples SPRED1-deleted? A deleted SPRED1 cannot be occupied, so copy number is a prerequisite check for any occupancy claim on this gene and was not run.
- PRE-REGISTERED FOR A LATER CYCLE, not run here: is the Q152 core enriched for RAS/MAPK regulators (GO:0043410 positive regulation of MAPK cascade and GO:0043409 negative regulation), scored against activity-matched draws from the same 332? EPHA7 and SPRED1 are the two widest-margin members after WT1 and sit on opposite sides of that pathway.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
SPRED1 is a reviewed human UniProt entry, accession Q7Z699, 444 residues, Sprouty-related EVH1 domain-containing protein 1.
UniProtKB Q7Z699 - Sprouty-related, EVH1 domain-containing protein 1 (Homo sapiens), reviewed · UniProt Consortium · UniProtKB/Swiss-Prot 2026What this evidence cannot show
gene_exact:SPRED1 returns one reviewed human record; no row in data/symbol-collisions.json (checked, 211 rows).
Evidence that argues against this (1)
- SPRED1 is the Legius syndrome gene and germline loss-of-function is common enough that a patient-derived sample may carry a variant or deletion; the accession describes the wild-type protein only. Olsson L et al. 2013
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
In GSE252378 the SPRED1 2 kb promoter (hg38 chr15:38,251,835-38,253,835, plus-strand refGene TSS 38,252,835, NM_152594) is occupied in 3 of 8 KMT2A::AFF1 samples (TB986292, p279, p454) at 2.03-4.54x and 0 of 19 non-AFF1 samples, with the highest non-AFF1 value 1.28x in A89691 and no non-AFF1 sample above 1.5x - a margin of 1.59, third widest of the 17 core promoters.
Q152 per-core-gene occupancy and separation margins over GSE252378 · Iqbal Lab oncofusion knowledge graph, beat Q152 · this project 2026What this evidence cannot show
Q152's permutation null shows a 3-of-8 AFF1-exclusive pattern is within the chance range. The coordinate is read directly from this project's promoters.tsv (TSS +/-1000, NM_152594); the window contains no other refGene TSS within 2 kb.
Evidence that argues against this (1)
- SPRED1 deletion is recurrent in paediatric B-ALL, and a deleted locus cannot be occupied. If any of the three occupied samples is SPRED1-deleted the call is an artefact, and if any of the 19 negative samples is deleted then its absence is trivially explained. Copy number was not checked. Olsson L et al. 2013
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In 307 consecutive uniformly treated paediatric ALL cases, deletions of SPRED1 were significantly more common in B-cell-precursor ALL patients who relapsed than in those remaining in complete remission, and SPRED1 deletion was associated in univariate analysis with decreased 10-year event-free survival and with poor overall survival; MLL rearrangement was associated with decreased event-free survival in the same analysis.
Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011 · Olsson L, Castor A, Behrendtz M, Biloglav A, Forestier E, Paulsson K, Johansson B · Leukemia 28:302-10 2013What this evidence cannot show
SNP-array deletion calling, not sequencing; IKZF1 and not SPRED1 was the independent risk factor in multivariate analysis, so the SPRED1 association is univariate only. No infant or KMT2A-rearranged subgroup is reported for SPRED1 specifically.
Evidence that argues against this (1)
- IKZF1 and not SPRED1 was the independent risk factor in the multivariate model, so the SPRED1 prognostic association may be carried by co-deletion with IKZF1 rather than by SPRED1 itself. Olsson L et al. 2013
named by this beat; third-widest margin at 1.59
- related to →KMT2A-rearranged acute lymphoblastic leukaemia
SPRED1 deletion marks relapse in paediatric B-cell-precursor ALL
opposite signs on the RAS/MAPK axis; both are wide-margin members of the same core, untested as a pathway