The same reader domain, mutated instead of fused, causes a childhood kidney tumour
also called MLLT1 YEATS Wilms · ENL YEATS mutation · Favourable Histology Wilms tumour MLLT1
The part of ENL that this project wants to drug is also broken in a kind of childhood kidney cancer — not by being fused to another gene, but by small mutations that change how it reads chromatin. The children affected are younger than average, and their tumours switch on the same genes.
The same thing, for a scientist
Recurrent mutations in the **highly conserved YEATS domain of MLLT1 (ENL)** occur in Favourable Histology Wilms tumour, an embryonal kidney tumour resembling developing kidney. The mutant protein shows **altered binding to acetylated histone tails**, and the tumours show **increased MYC expression and HOX dysregulation** — the same output program this graph tracks in KMT2A-rearranged leukaemia. Affected children present younger and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model of activating MLLT1 mutation **early in renal development**.
Why this is an analogy worth holding
This graph reasons about ENL almost entirely as a fusion partner — KMT2A::MLLT1 is one of the commonest 3' partners, and target-phase2-enl-yeats-dossier proposes drugging its YEATS domain. Wilms tumour reaches the same domain by a completely different route: point mutation of the reader itself, with no fusion and no KMT2A involvement at all.
Three features converge with the leukaemia biology:
| KMT2A::MLLT1 leukaemia | MLLT1-YEATS-mutant Wilms | |
|---|---|---|
| lesion | translocation, ENL joined to the KMT2A N-terminus | point mutation inside the YEATS domain |
| proximate defect | mislocalised elongation machinery | altered binding to acetylated histone tails |
| output | HOXA dysregulation | HOX dysregulation and increased MYC |
| timing | in utero or first year of life | early in renal development, with precursor nephrogenic rests |
Both are developmental tumours of chromatin reading that converge on HOX. That is a genuine cross-family analogy of the kind this project collects, and it arrives at the domain an active dossier proposes to inhibit.
Which direction it cuts for drugging ENL
For. The YEATS domain is now an oncogenic driver in two distinct paediatric malignancies by two distinct mechanisms. A reader domain whose perturbation drives disease in kidney and blood is a domain whose function is load-bearing in transformation, and a YEATS inhibitor would have a second paediatric indication with a clean genetic rationale.
Against, and this is the sharper reading. The Wilms mutations are activating — they change what the domain binds, not whether it binds. A tumour caused by a gain of altered reading tells you the domain matters; it does not tell you that losing it is tolerated, which is the question an inhibitor asks. The two experiments are on different axes, and the Wilms data speak to the axis the dossier does not need.
It also complicates the normal-tissue reading. ana-normal-tissue-exposure found MLLT1 peaks in cerebellum at 142 TPM, the highest brain value of any target in this graph, in a disease of the first year of life. Wilms shows ENL is consequential during organ development. Neither fact establishes harm from inhibition, and together they raise the question rather than answering it.
- Read PMC for PMID 26635203 and record the actual mutation spectrum. Which YEATS residues, at what recurrence, and do they overlap the acetyl-lysine binding pocket that `target-phase2-enl-yeats-dossier` proposes to occupy? If an inhibitor and a mutation compete for the same pocket, that is a structural argument the dossier should carry.
- Does a YEATS inhibitor work on MLLT1-mutant Wilms cells? If the mutation alters rather than abolishes binding, an inhibitor might be more effective there than in fusion leukaemia, which would be a second indication with a cleaner genetic case.
- Is there a germline MLLT1 phenotype? Seven records answer an MLLT1 germline/syndrome query and none was read. A human loss-of-function phenotype would bear directly on whether ENL inhibition is developmentally safe — the question GTEx cannot answer.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Recurrent mutations within the highly conserved YEATS domain of MLLT1 (ENL) occur in Favourable Histology Wilms tumour. The mutant protein shows altered binding to acetylated histone tails; mutant tumours show increased MYC expression and HOX dysregulation; and affected patients present at a younger age with a high prevalence of precursor intralobar nephrogenic rests, supporting activating MLLT1 mutation early in renal development.
MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours · Nature Communications 2015What this evidence cannot show
Abstract read from the NCBI efetch record on 2026-09-19 by the coordinator; full text not read, so the mutation spectrum, recurrence frequency and cohort size are not recorded here and should not be quoted from this item. 'Recurrent' and 'high prevalence' are the authors' words without numbers attached in the abstract. The tumour is a kidney malignancy and every transfer to leukaemia is an analogy, not an import.
Evidence that argues against this (2)
- The mutations are **activating** and an inhibitor asks the opposite question. Altered acetyl-lysine binding causing a tumour establishes that the YEATS domain's reading function is consequential; it says nothing about whether abolishing that function is tolerated in a developing child, which is what a YEATS inhibitor would do. Gain-of-altered-function and loss-of-function are different axes and this paper is on the one the dossier does not need. Journal of Molecular Biology 2022
- HOX dysregulation and raised MYC are among the least specific readouts in cancer biology and are shared by a very large number of paediatric and adult tumours with unrelated drivers. Convergence on HOX between Wilms and KMT2A-rearranged leukaemia is therefore weak evidence of shared mechanism, and the analogy should rest on the domain identity rather than on the output program. Nature Communications 2015
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
MLLT1 (ENL) and its paralogue MLLT3 (AF9) are YEATS-family epigenetic readers that bind acetylated and crotonylated lysines, unlike bromodomains which bind only acetylated lysines, and carry documented roles across normal haematopoiesis, MLL-fusion leukaemia and kidney cancer. MLL-AF9 and MLL-ENL fusions are reported in approximately 34% and 31% of MLL-fusion AML and ALL patients respectively.
The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer · Journal of Molecular Biology 2022What this evidence cannot show
Abstract read on 2026-09-19; full text not read. This is a review, so the 34% and 31% figures are secondary and are not attributed to a named cohort in the abstract; they should not be quoted as primary frequencies against this graph's own recombinome-derived numbers, which come from 3,401 patients and are cited elsewhere. The crotonyl-reading distinction from bromodomains is a general YEATS family property.
Evidence that argues against this (1)
- Partner frequencies quoted in reviews diverge from the primary series this graph already holds: the 2023 KMT2A recombinome, read in full, gives the seven most frequent partners plus PTDs as more than 90% of all recombinations across 3,401 patients, with a partner distribution strongly dependent on age and lineage. A single pair of percentages without a cohort behind them should not be carried forward. Nature Communications 2015
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MLLT1 is independently confirmed as a recurrently mutated Wilms tumour gene by a second and much larger study: the Children's Oncology Group and TARGET initiative sequenced 651 Wilms tumours and lists MLLT1 among the genes previously implicated in Wilms tumour alongside WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MYCN and TP53.
A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor · Nature Genetics 2017What this evidence cannot show
Abstract read by the coordinator on 2026-09-19; full text not read, so the MLLT1 mutation frequency within the 651 tumours is not recorded here and must not be quoted from this item. The abstract lists MLLT1 among genes *previously* implicated rather than newly discovered, so this is independent confirmation of recurrence in a large cohort and not an independent discovery.
Evidence that argues against this (1)
- Appearing on a list of previously implicated genes is the weakest form of confirmation available. The abstract's emphasis is on the genes it found that were NOT previously recognised - BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, ARID1A - and MLLT1's frequency in this cohort could be low without the abstract saying so. Nature Genetics 2017
ENL YEATS hotspot condensates, no phospho link