TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away

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.

• If TET1 keeps CpG islands unmethylated and thereby maintains the fusion's address, a TET inhibitor would be predicted to CLOSE the address - and would simultaneously raise 5mC genome-wide, which is the change that produced H3K9me3 and silencing at Hoxa9 in the swap experiment. The therapeutic direction and the toxic direction are the same direction.
• TET1 is up-regulated by the fusion in one literature and dispensable in another. A programme built on the first would be building on a result the second contradicts with a better-controlled genetic tool.
• Any CXXC-directed small molecule hits TET1's domain too. Depleting TET1 activity in a developing child touches an enzyme with a documented role in tissue-specific demethylation, and the paediatric safety case for that has never been made.

1. Which TET1 isoform is expressed in KMT2A-rearranged blasts? If it is TET1ALT, the protein present has no CXXC domain and cannot be a competitor for the address at all - and that is a single RNA-seq junction query away on existing infant ALL data.
2. Do the MLL-AF9 and MLL-ENL Tet1 results differ because of the fusion, the knockout design, or the timing of deletion? A conditional Tet1 deletion in an established MLL-AF9 leukaemia would separate initiation from maintenance.
3. Does TET1 depletion change KMT2A-fusion occupancy at shared CpG islands? Nobody has run the ChIP.
4. Is the KMT2A::TET1 fusion's coiled coil sufficient for transformation on its own, as the dimerisation class predicts, and does the absence of TET1's CXXC make this fusion behave like MLL-SEPT6 rather than like MLL-AF4?
5. Do the reported KMT2A::TET1 genomic breakpoints all fall 5' of TET1's CXXC domain, as the 2002 index transcript does? Four clinical reports exist and none was read in this beat; reading them is the cheapest way to settle whether any KMT2A fusion has ever carried a second CXXC domain.

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

   TET1 (Q8NFU7) is 2,136 aa with a CXXC-type zinc finger at 584-625; its unscoped nuclear location comment is ECO:0000250 while the experimental ECO:0000269 nuclear calls are isoform-scoped; and the curated DOMAIN comment states the CXXC participates in CpG-DNA binding while global chromatin binding can occur without it.

   UniProtKB Q8NFU7 (TET1_HUMAN), Methylcytosine dioxygenase TET1 / CXXC-type zinc finger protein 6 / Leukemia-associated protein with a CXXC domain · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   Fetched 2026-09-21; accession resolved by gene_exact:TET1 AND organism_id:9606 AND reviewed:true with gene_primary requested and read back as TET1, one row returned, length 2136 confirmed from the same record. UniProt feature boundaries come from a sequence model, not from a structure of this protein. Per rule 91 the evidence codes were read per comment, including the uncoded ones, and the isoform-scoped statements are recorded here rather than discarded.

   ▸Evidence that argues against this (1)

   • The isolated-domain binding literature gives the CXXC a larger role than the full-length chromatin data does; Arand et al. show the zinc finger's dominant in-vivo effect is exclusion from replicating heterochromatin rather than recruitment to CpG islands. Arroyo M et al. 2022
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   TET1, described in the title as a fusion partner of the MLL gene in acute myeloid leukaemia, is a 2-oxoglutarate- and Fe(II)-dependent enzyme that converts 5-methylcytosine to 5-hydroxymethylcytosine in cells and in vitro.

   Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. · Tahiliani M, Koh KP, et al. · Science 2009
   PMID 19372391DOI
   ▸What this evidence cannot show

   The enzymology is in HEK293 cells and in vitro with recombinant protein, and the 5hmC measurement is in mouse ES cells. Nothing in this paper is a leukaemia experiment; the MLL connection in the title is bibliographic, citing the 2002 cloning.

   ▸Evidence that argues against this (1)

   • UniProt records an unresolved CAUTION that the steps downstream of 5hmC in cytosine demethylation are disputed between a deamination/base-excision model and an iterative-oxidation model, so 'TET1 demethylates DNA' remains a model rather than a settled pathway. UniProt Consortium 2026
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   TET1 was cloned as LCX, fused to MLL in a de novo adult AML-M2 with trilineage dysplasia carrying t(10;11)(q22;q23), and the MLL-LCX fusion protein lacked LCX's CXXC domain while retaining its C-terminal alpha-helical coiled coil.

   LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). · Ono R, Taki T, et al. · Cancer Res 2002
   PMID 12124344
   ▸What this evidence cannot show

   A single index case. The fusion transcript structure is from RT-PCR and cDNA analysis of one patient, so 'the fusion lacks the CXXC domain' is a statement about this breakpoint and not necessarily about every KMT2A::TET1 breakpoint. No functional experiment in this paper.

   ▸Evidence that argues against this (1)

   • A later report states that an MLL-TET1 fusion protein promotes immortalisation of myeloid progenitors and leukaemia development, which implies the construct used was functional; that letter carries no PubMed abstract, so the construct's domain content could not be checked from the record. Kim HS et al. 2017
4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   TET1 is a direct target of MLL-fusion proteins, is significantly up-regulated in MLL-rearranged leukaemia with a global increase in 5hmC, and is reported as indispensable for MLL-rearranged leukaemia development through Hoxa9, Meis1 and Pbx3.

   TET1 plays an essential oncogenic role in MLL-rearranged leukemia. · Huang H, Jiang X, et al. · Proc Natl Acad Sci U S A 2013
   PMID 23818607DOI
   ▸What this evidence cannot show

   Murine MLL-fusion myeloid models plus human MLL-rearranged AML expression data. Conventional Tet1 knockout. Nothing in infant B-lineage KMT2A::AFF1. The word 'indispensable' rests on the knockout used, which the 2021 conditional study disputes.

   ▸Evidence that argues against this (1)

   • Conditional Tet1 ablation in HSCs expressing MLL-ENL, and in progenitors transduced with MLL-ENL, did not critically affect leukaemic immortalisation, directly contradicting the indispensability claim. Ono R et al. 2021
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In newly generated conditional Tet1-knockout mice crossed to inducible MLL-ENL transgenics, leukaemic immortalisation in vitro was not critically affected by Tet1 ablation in haematopoietic stem cells or in retrovirally transduced progenitors.

   Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models. · Ono R, Masuya M, et al. · PLoS One 2021
   PMID 33705482DOI
   ▸What this evidence cannot show

   Murine MLL-ENL myeloid system; a different fusion from the one used in the positive report. A negative result in one fusion does not exclude a requirement in another, and the paper's own framing is that it examined the role 'more precisely' rather than that the earlier result was wrong.

   ▸Evidence that argues against this (1)

   • Huang et al. report the opposite conclusion with in-vitro and in-vivo functional data in MLL-fusion models and a named downstream axis. Huang H et al. 2013
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   TET1 has an isoform transcribed from an alternative promoter in intron 2 that lacks the CXXC domain but retains the catalytic domain, is the predominantly activated isoform in several cancers, and produces 5hmC with weaker effects on DNA methylation than full-length TET1.

   A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. · Good CR, Madzo J, et al. · Nucleic Acids Res 2017
   PMID 28531272DOI
   ▸What this evidence cannot show

   Isoform-specific expression is measured by RNA-level assays and overexpression; the cancer types are breast, uterine and glioblastoma, not leukaemia. No leukaemia cohort is analysed, so whether TET1ALT or TET1FL is the species present in KMT2A-rearranged blasts is unknown.

   ▸Evidence that argues against this (1)

   • Liu et al. report that in vivo Tet1 isoforms with and without the CXXC domain hydroxylate genomic 5-methylcytosine with similar activity, which argues the isoform difference is about targeting rather than output. Liu N et al. 2013
7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Full-length Tet1 is tethered away from heterochromatin by its zinc-finger domain, which the short isoform Tet1s lacks; Tet1s is instead ubiquitinated by CRL4(VprBP), recognised by Uhrf1 and recruited to replicating heterochromatin, producing aberrant cytosine-modification levels.

   Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation. · Arroyo M, Hastert FD, et al. · Nat Commun 2022
   PMID 36056023DOI
   ▸What this evidence cannot show

   Human and mouse cell lines with imaging and biochemistry; not a leukaemia system. The claim is about subnuclear compartment during replication, not about CpG-island occupancy.

   ▸Evidence that argues against this (1)

   • The same laboratory's earlier work reports MBD1's CXXC3 domain positively regulating Tet1 heterochromatin localisation, so the zinc-finger 'exclusion' model needs the partner context to be complete. Zhang P et al. 2017
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   TET1 shows no selective dependency in KMT2A-rearranged cell lines: difference -0.0056 between arms, rank 9,875 of 17,728, and pan-essentiality -0.0154 across 1,208 lines.

   Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap CRISPR Chronos via the Open Targets Platform GraphQL API) · Oncofusion knowledge-graph project · analyses/depmap-kmt2a-selective-scan-full/results.json, generated 2026-09-19; Open Targets dataVersion year 26 month 06, re-read from the API on 2026-09-21 2026
   ▸What this evidence cannot show

   The scan compares 11 Cellosaurus-annotated KMT2A-rearranged lines against 43 other leukaemia lines; none of the 11 is infant-derived and the arm is myeloid-enriched, so a difference mixes fusion status with lineage. Both the difference and the pan-essentiality across all 1,208 lines are quoted, because a gene required everywhere is not a selective dependency. Open Targets dataVersion 26.06; DepMap's own release identifier is not returned by that endpoint.

   ▸Evidence that argues against this (1)

   • Murine functional work reports Tet1 as indispensable for MLL-rearranged leukaemia; a cell-line CRISPR screen in established lines cannot detect a requirement that acts at initiation rather than maintenance. Huang H et al. 2013
9. E9weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

   An MLL-TET1 fusion protein has been reported to promote immortalisation of myeloid progenitor cells and leukaemia development.

   MLL-TET1 fusion protein promotes immortalization of myeloid progenitor cells and leukemia development. · Kim HS, Oh SH, et al. · Haematologica 2017
   PMID 28798069DOI
   ▸What this evidence cannot show

   A Letter with no abstract in the PubMed record, so the construct's domain content, the model and the controls could not be read from the record retrieved here and the paper itself was not read. Recorded per the project's 'found, on topic, not read' rule; do not build on it.

   ▸Evidence that argues against this (1)

   • The index clinical case reports that the MLL-LCX fusion transcript lacked LCX's CXXC domain, so any construct that includes it is not the patient species. Ono R et al. 2002
10. E10moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    TET1 overexpression in MLL-rearranged AML also depends on MYC-mediated transcriptional repression of miR-26a, which otherwise negatively regulates TET1 post-transcriptionally.

    Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia. · Huang H, Jiang X, et al. · Cancer Lett 2016
    PMID 26791235DOI
    ▸What this evidence cannot show

    Same laboratory as the positive dependency claim, so this is corroboration within one group rather than independent replication. Human MLL-rearranged AML cell lines and murine transformation assays; no infant B-lineage material.

    ▸Evidence that argues against this (1)

    • If Tet1 is dispensable for MLL-ENL leukaemogenesis, a circuit that raises TET1 levels may be a consequence of the fusion's transcriptional programme rather than a required arm of it. Ono R et al. 2021
11. E11strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    TET1's CXXC domain was measured alongside every other human CXXC domain for DNA-binding selectivity, placing it in a defined selectivity class within the family.

    DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants. · Xu C, Liu K, et al. · Structure 2018
    PMID 29276034DOI
    ▸What this evidence cannot show

    Isolated domains, short duplex substrates, in vitro. Affinity of a domain out of its protein does not predict genomic occupancy.

    ▸Evidence that argues against this (1)

    • A direct MLL1-versus-TET3 comparison found that earlier CXXC specificity measurements had not controlled for interference from cytosines elsewhere in the substrate, so family-wide selectivity rankings carry an uncontrolled variable. Stroynowska-Czerwinska A et al. 2018
12. E12strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In the MLL-AF9 CXXC-swap experiment, what distinguished functional from non-functional substitutions was which CpG residues were protected from methylation, which prevented H3K9me3 and enabled Hoxa9 expression.

    Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia. · Risner LE, Kuntimaddi A, et al. · J Biol Chem 2013
    PMID 23990460DOI
    ▸What this evidence cannot show

    Murine MLL-AF9 myeloid system; three heterologous domains tested. The mechanism is inferred from bisulphite and ChIP readouts on one locus (Hoxa9), not genome-wide.

    ▸Evidence that argues against this (1)

    • All substituted fusions still targeted Hoxa9, so locus targeting and leukaemogenicity separate in this experiment and 'the address' is not sufficient on its own. Risner LE et al. 2013
13. E13weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    TET1, a member of a novel protein family, is reported fused to MLL in acute myeloid leukaemia containing t(10;11)(q22;q23).

    TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). · Lorsbach RB, Moore J, et al. · Leukemia 2003
    PMID 12646957DOI
    ▸What this evidence cannot show

    A Letter/Case Report with NO abstract in the PubMed record retrieved this session, so nothing about its content was read and nothing is asserted from it beyond the title. Recorded under this project's 'found, on topic, cannot be read from the record' rule at weak confidence; do not build on it without reading the paper.

    ▸Evidence that argues against this (1)

    • The index cloning paper states the MLL-LCX fusion transcript lacks LCX's CXXC domain, so a reader should not assume any of these clinical cases carries a fusion with two CXXC domains. Ono R et al. 2002
14. E14weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    A dedicated report describes genomic breakpoints and clinical features of MLL-TET1 rearrangement in acute leukaemias.

    Genomic breakpoints and clinical features of MLL-TET1 rearrangement in acute leukemias. · Lee SG, Cho SY, et al. · Haematologica 2013
    PMID 23100278DOI
    ▸What this evidence cannot show

    A Letter/Case Report with NO abstract in the PubMed record retrieved this session, so nothing about its content was read and nothing is asserted from it beyond the title. Recorded under this project's 'found, on topic, cannot be read from the record' rule at weak confidence; do not build on it without reading the paper.

    ▸Evidence that argues against this (1)

    • Breakpoint coordinates in a Letter were not read here, so this graph still cannot say whether the reported breakpoints preserve or remove TET1's CXXC domain - which is the only thing about this fusion that matters to this beat. Ono R et al. 2002
15. E15weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    A t(10;11)(q22;q23)/MLL-TET1 translocation has been described in a T-cell lymphoblastic lymphoma with a subsequent lineage switch to acute myelomonocytic myeloid leukaemia.

    First description of the t(10;11)(q22;q23)/MLL-TET1 translocation in a T-cell lymphoblastic lymphoma, with subsequent lineage switch to acute myelomonocytic myeloid leukemia. · Ittel A, Jeandidier E, et al. · Haematologica 2013
    PMID 24323992DOI
    ▸What this evidence cannot show

    A Letter/Case Report with NO abstract in the PubMed record retrieved this session, so nothing about its content was read and nothing is asserted from it beyond the title. Recorded under this project's 'found, on topic, cannot be read from the record' rule at weak confidence; do not build on it without reading the paper.

    ▸Evidence that argues against this (1)

    • A single case with a lineage switch is the kind of report that generalises badly, and lineage switch is itself a recognised feature of KMT2A-rearranged disease independent of the partner. Ono R et al. 2002

• ← fuses withKMT2A::TET1 (MLL-LCX), t(10;11)(q22;q23) — the fusion that throws away a second CXXC domain

  The 3' partner. TET1 is one of the twelve human CXXC-domain proteins, and the fusion DISCARDS its CXXC while keeping the alpha-helical coiled coil - so a join between two CpG readers yields a chimera with exactly one CpG reader, KMT2A's. TET1's own entry additionally records it as a disputed fusion dependency: indispensable in conventional-knockout MLL-AF9 work and not required in purpose-built conditional-knockout MLL-ENL mice.

• related to →The CXXC domain (aa 1147-1195, PDB 2KKF) is a chromatin address, not a compartment address — CpG mutants lose transformation but keep their subnuclear position

  TET1's CXXC domain (Q8NFU7 584-625) reads the same unmethylated-CpG address, and full-length TET1 maintains it by protecting CpG islands from methylation.

• related to →CXXC to unmethylated CpG DNA: nine mapped contact residues, and an affinity that spans 44 uM to 33 nM depending on the construct, the DNA and the salt

  One of the eleven other human CXXC domains any ligand for this interface would have to discriminate against.

• fuses with →KMT2A / MLL1 — the gene that breaks

  t(10;11)(q22;q23) MLL-LCX in AML-M2 with trilineage dysplasia; the fusion protein lacks TET1's own CXXC domain and retains its coiled coil.

• part of →The human CXXC/CpG-reading family is exactly twelve proteins, and TET2 is not one of them

  One of the twelve human CXXC proteins.

• related to →Step 1 — How the fusion finds its genes: AT-hooks and the CXXC domain reading unmethylated CpG

  The fusion's CpG-island target set is a read-out of the methylation landscape; TET1 is one of the enzymes that sets it.

• related to →TET3 - the CXXC reader whose domain prefers 5-carboxylcytosine, and the only CXXC-family gene ever found mutated in a KMT2A-rearranged cohort

  The two TET paralogues that do carry a CXXC domain; TET2 does not.

• ← related toTET2 is NOT a CXXC protein - its CXXC domain is a separate gene, and it is DEPLETED in KMT2A-rearranged AML rather than enriched

  Same enzyme family, opposite status in the CXXC census and opposite direction in KMT2A-rearranged leukaemia - TET1 reported up-regulated, TET2 mutations depleted.

• ← regulatesMBD1 - one protein with a methyl-CpG reader and three CXXC fingers, only the third of which binds unmethylated CpG, and whose CXXC fails the MLL-AF9 swap

  MBD1's CXXC3 enhances TET1 heterochromatin localisation and 5mC oxidation; TET1 activity then displaces MBD1 - the family's one documented reciprocal occupancy cycle.

• ← inhibitsIDH2 - the hypermethylating co-mutation that IS enriched in KMT2A-rearranged AML (16.0% vs 10.4%), at p = 0.0004 and not the p < 0.0001 the abstract claims

  2-HG is a competitive inhibitor of the TET family as a class, not of TET2 alone.