AnalysisestablishedQ92-kmt2a-sarcoma

Which KMT2A exon carries which interface: exon 1 is the menin-binding motif, exons 5-6 are the CXXC zinc finger (computed, not recalled)

also called KMT2A exon-to-domain map · KMT2A exon 1 menin-binding motif · KMT2A exons 5-6 CXXC

Every paper on KMT2A-rearranged sarcoma describes its fusions by exon number, while this project describes KMT2A by protein domain, so the two cannot be compared until the exons are translated into residues. This entry does that translation once, from live Ensembl and UniProt records, so other entries cite it instead of guessing.

The same thing, for a scientist

KMT2A fusion breakpoints in the sarcoma literature are reported as exon indices (NM_001197104 / ENST00000534358), whereas this graph's mechanism layer is written in UniProt Q03164 residue coordinates. Mapping the canonical 36-exon CDS to codon ranges and intersecting with the Q03164 feature table gives the assignments that decide whether a given sarcoma fusion can engage menin at all: the menin-binding motif (MBM, aa 6-25) and the LEDGF/PSIP1 integrase-binding motif 1 (IBM1, aa 123-134) lie wholly inside EXON 1; IBM2 (aa 147-152) lies in EXON 2; all three AT-hooks (169-180, 217-227, 301-309) lie in the single large EXON 3; and the CXXC-type zinc finger (aa 1147-1195) straddles EXONS 5-6. The leukaemia breakpoint cluster region sits downstream, in exons 8-14. Consequence: a fusion whose KMT2A contribution starts at exon 2 or later cannot contain the menin-binding motif, and a fusion contributing only exons 5-6 contains the CXXC zinc finger and essentially nothing else.

Go deeper

The map

KMT2A feature	UniProt Q03164 residues	exon(s)
Menin-binding motif (MBM)	6-25	1
IBM1 (LEDGF/PSIP1 integrase-binding motif 1)	123-134	1
IBM2	147-152	2
AT-hook 1 / 2 / 3	169-180 / 217-227 / 301-309	3 (all three)
CXXC-type zinc finger	1147-1195	5-6
leukaemia breakpoint cluster region	~1338-1607	8-14
SET	3829-3945	34-36

Exon-to-codon boundaries 1; feature coordinates 2. The exon indices the field uses for the CXXC domain and the breakpoint cluster region are stated in the sarcoma literature itself and match the computed map independently 3.

Why the 3-residue discrepancy does not matter here

ENST00000534358 translates to 3,972 aa and UniProt Q03164 is 3,969 aa. Aligning the two sequences puts the first mismatch at residue 1604 - a 3-residue insertion in the Ensembl translation. Residues 1-1603 are therefore numbered identically in both frames, which covers every feature that decides menin and LEDGF engagement, and the CXXC zinc finger as well 12. This is the residue-offset trap that has bitten this project before (the 94-residue ASH2L offset); it was checked rather than assumed.

What it implies for the index fusion, by contrast

In KMT2A::AFF1 and every other leukaemogenic KMT2A fusion the break is in exons 8-14, so the retained 5' KMT2A fragment necessarily includes exon 1 and therefore the menin-binding motif, both LEDGF integrase-binding motifs and all three AT-hooks. The sarcoma fusions break on the far side of exon 1 or discard it entirely. That single exon is the difference between a KMT2A rearrangement this project's model applies to and one it does not.

Facts and figures

script	computed inline (Ensembl REST + UniProt REST), 2026-09-21
status	run
method	Computed 2026-09-21 from Ensembl REST: KMT2A canonical transcript ENST00000534358 (36 exons, 3,972 aa) CDS exon boundaries mapped to codon ranges, then intersected with the UniProt Q03164 (3,969 aa) feature table. Exon 1 = aa 1-144; exon 2 = 145-168; exon 3 = 168-1052; exon 4 = 1053-1112; exon 5 = 1112-1190; exon 6 = 1190-1212; exon 7 = 1212-1338. The two sequences are IDENTICAL over residues 1-1603 (first mismatch at 1604, a 3-residue insertion in the Ensembl translation), so the domain-to-exon assignment is unaffected by the length difference.
result summary	MBM aa 6-25 and IBM1 aa 123-134 are in exon 1; IBM2 aa 147-152 in exon 2; AT-hooks 1-3 all in exon 3; CXXC zinc finger aa 1147-1195 in exons 5-6; leukaemia breakpoint cluster in exons 8-14. The two reference sequences are identical over aa 1-1603.
uniprot	Q03164
length AA	3969
ensembl gene ID	ENSG00000118058
ensembl transcript ID	ENST00000534358

inputs

[
  "Ensembl ENST00000534358 (KMT2A canonical, 36 exons, 3972 aa)",
  "UniProt Q03164 (KMT2A, 3969 aa)"
]

exon AA ranges

{
  "1": [
    1,
    144
  ],
  "2": [
    145,
    168
  ],
  "3": [
    168,
    1052
  ],
  "4": [
    1053,
    1112
  ],
  "5": [
    1112,
    1190
  ],
  "6": [
    1190,
    1212
  ],
  "7": [
    1212,
    1338
  ],
  "8": [
    1338,
    1362
  ]
}

How this could bite us back

A menin-inhibitor rationale built on 'this tumour has a KMT2A rearrangement' is refuted by this map alone if the rearrangement excludes exon 1: the drug's target interface is not present in the fusion protein. Checking one exon index costs nothing and a trial costs years.
The converse error is equally available. Reading 'CXXC retained' as 'behaves like a leukaemia fusion' ignores that leukaemia fusions retain exon 1 as well, and the CXXC domain alone has never been shown to transform anything.

Still open

Does any reported KMT2A fusion in a solid tumour retain exon 1, and therefore the menin-binding motif? The reciprocal 5' KMT2A products reported in YAP1-rearranged sarcoma (KMT2A exon 3, 4 or 6 joined to YAP1) are the only published candidates and none has been tested for menin binding.
The CXXC zinc finger straddles the exon 5/6 boundary at aa 1190. Does a fusion including exon 5 but not exon 6 produce a truncated, non-functional CXXC, and is that why one published case was out-of-frame for exon 6?

Every source behind this entry (3)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Computed here from live Ensembl REST (2026-09-21): in the CDS of KMT2A canonical transcript ENST00000534358, exon 1 encodes aa 1-144, exon 2 encodes aa 145-168, exon 3 encodes aa 168-1052, and exons 5-6 together encode aa 1112-1212.
Ensembl REST API lookup, KMT2A (ENSG00000118058), canonical transcript ENST00000534358 with exon and translation coordinates · Ensembl (EMBL-EBI) · Ensembl REST 2026
What this evidence cannot show
Exon indices are transcript-specific. The sarcoma literature states it converted its nomenclature to NM_001197104, the RefSeq counterpart of this 36-exon transcript; an entry reading an exon index off a paper that names a different transcript must re-derive it. Codon ranges were computed by cumulative CDS length, so a codon split across an exon boundary is listed in both flanking exons.
Evidence that argues against this (1)
- A different KMT2A transcript renumbers every exon. The older MLL literature numbers the breakpoint cluster region as introns 9-11 while the pathology literature used here calls it exons 8-14 - the same physical region under two conventions. Any exon number quoted from a paper is only as good as the transcript that paper names. Massoth LR et al. 2020
E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Computed here from live UniProt REST (2026-09-21): Q03164 (KMT2A, primary gene name read back as KMT2A, 3,969 aa) annotates a menin-binding motif at aa 6-25, IBM1 at 123-134, IBM2 at 147-152, AT-hooks at 169-180, 217-227 and 301-309, and a CXXC-type zinc finger at 1147-1195.
UniProtKB Q03164 (KMT2A_HUMAN), Histone-lysine N-methyltransferase 2A, feature table and sequence · UniProt Consortium · UniProtKB 2026
What this evidence cannot show
The primary gene name and the length were read back from the fetched record per this project's accession discipline. Motif boundaries are UniProt curation; the functional menin contact is narrower than aa 6-25 (the MBM1 core is RWRFP, aa 6-10), so 'inside exon 1' is robust while the exact motif edges are not load-bearing here.
Evidence that argues against this (1)
- UniProt's Q03164 sequence is 3 residues shorter than the Ensembl canonical translation, so a naive join of a paper's exon index to a UniProt residue can be off by 3 above aa 1603. Resolved here by aligning the two sequences and locating the single mismatch; entries relying on coordinates above 1603 must repeat that step. Ensembl (EMBL-EBI) 2026
E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In a pan-sarcoma KMT2A study the authors state that in KMT2A-rearranged leukaemia the breakpoints lie primarily in exons 8-14, preserving both the CxxC-binding domain in exons 5-6 and the adjacent repression domain 2 largely encoded by exons 7-8.
Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions. · Massoth LR, Hung YP, Nardi V, et al. · Mod Pathol 2020
PMID 32461620 DOI
What this evidence cannot show
This is the pathologists' summary of the leukaemia literature inside a sarcoma paper, not a primary breakpoint census. It is cited only to fix which exon indices the field uses for the CXXC domain and the breakpoint cluster region, and it agrees with the independently computed map in E1-E2.
Evidence that argues against this (1)
- A companion series on the same entity states the leukaemia breakpoints as 'between exon 9 and intron 11' rather than exons 8-14. Both describe the same 8.3 kb region under different exon conventions, which is precisely why this entry computes residues rather than trusting an index. Kao YC et al. 2020

Connected to

← depends onThe clock/SIRT1-regulated MLL1 acetylation site maps to KMT2A K1130 and K1133 in human numbering, just N-terminal to the CXXC and 208 residues before the breakpoint cluster - so it is retained in every KMT2A fusion
the CXXC and breakpoint-cluster coordinates this placement rests on
← depends onEvery MS-evidenced KMT2A modification site, flagged retained or lost against the breakpoint - and the retained portion is NOT enriched for acetylation once you use the right null
uses its exon 7/8 boundary at aa 1338 as the retained/lost cut
part of →KMT2A / MLL1 — the gene that breaks
exon-to-residue map of KMT2A's interfaces (exon 1 = MBM, exons 5-6 = CXXC)
supports →YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away
translates the reported exon breakpoints into the domains the fusion can encode
related to →MEN1 / menin — the adaptor the fusion cannot work without
locates the menin-binding motif (aa 6-25) in KMT2A exon 1, the exon sarcoma fusions discard
related to →PSIP1 / LEDGF p75 — the tether with the best therapeutic index in the whole interactome
locates IBM1 (aa 123-134) in exon 1 and IBM2 (aa 147-152) in exon 2
← depends onVIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon
the exon-to-residue translation that places the menin motif in the discarded exon 1
← depends onIn leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that.
the exon-to-residue map the polarity argument is computed from
← depends onLDB1::KMT2A - the clearest statement in this literature that a sarcoma fusion keeps KMT2A exons 4 to 36 and discards exons 1 to 3
exon 4 = codon 1053, which is how the retained domains were assigned
← depends onDOCK10 (Zizimin-3) - the Cdc42/Rac1 exchange factor fused to KMT2A exon 8 in an undifferentiated pleomorphic sarcoma, and the only one of the seven this graph already held as an H3K79me2-marked gene
the retained-module claim is a coordinate derivation against that map, re-verified here from NM_001197104.2
← depends onAHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon
retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2
← depends onELP4 (PAXNEB) - a required subunit of Elongator, the one partner of the seven with a genuine histone-acetyltransferase connection, and the one whose fusion supplies only its last 43 residues
retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2
← depends onCPT1A - the outer-mitochondrial-membrane fatty-acid gatekeeper that is also a lysine succinyltransferase, fused to KMT2A exon 3 in the one case that is tether WITHOUT address
the CXXC-loss call rests on exons 5-6 = aa 1112-1212, reproduced from NM_001197104.2 this cycle
← depends onC2CD3 - the centriole-elongation regulator fused to KMT2A exon 8 in an MPNST, predicted OUT OF FRAME, and the partner whose RefSeq transcript is 390 residues shorter than UniProt's canonical
retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2
← depends onTMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall
retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2
← depends onRALGAPA2 (AS250) - the catalytic brake on RalA that behaves as a tumour suppressor, fused to KMT2A exon 22 in an osteosarcoma and predicted out of frame, which makes allele DISRUPTION the better hypothesis than a chimera
retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2
← depends onSeven KMT2A-rearranged sarcomas retain the menin-binding motif, three of them carry the complete leukaemic N-terminal module, and all sixteen partner names were in one unopened supplementary table
USES IT AS THE INSTRUMENT: every domain call here is the source table's exon number resolved against this map (exon 1 = aa 1-144 with MBM 6-25 and IBM1 123-134; exon 2 = 145-168 with IBM2 147-152; exon 3 = 168-1052 with all three AT-hooks; exons 5-6 = 1112-1212 with CXXC 1147-1195). The MBM call is robust to transcript choice because every 5-prime breakpoint is at exon 3 or later; the CXXC and AT-hook calls are not.