MLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)
also called AF1q · AF1Q · ALL1-fused gene from chromosome 1q · Tcf7c · AF1Q_HUMAN
AF1q is one of the smallest proteins in the human genome that causes a cancer when it gets stuck onto another gene — just 90 building blocks long, with no part that touches DNA and no part that makes copies of itself stick together. It is the partner that none of the standard explanations for KMT2A leukaemia can account for.
The same thing, for a scientist
MLLT11 (UniProt Q13015, AF1Q_HUMAN, 90 aa) is the shortest KMT2A fusion partner in routine clinical use. Its UniProt record annotates **one** feature in the whole protein — a nuclear export signal at aa 24-32 — and no domain, no coiled coil, no repeat, and no PDB structure [E1]. The founding report described a predicted 9 kDa product with no similarity to any other protein in the databanks, an mRNA highly expressed in thymus but not peripheral lymphoid tissue, and expression in every leukaemic cell line tested [E2]. What is known about the protein since is mostly non-leukaemic: it shuttles (pronounced karyophily but constitutive nuclear export followed by ubiquitin-mediated degradation in the centrosomal area), it promotes T- over B-lineage output from multipotent human progenitors by increasing susceptibility to Delta-like/Notch signalling, and enforced expression in humanised mice expands BM CD34+CD7+ prothymocytes while silencing shifts lymphopoiesis toward B cells [E3]; it is degraded by chaperone-mediated autophagy via a KFERQ-like motif recognised by HSPA8/LAMP-2A [E4]; it binds the HMG domain (residues 154-237) of TCF7, activating CD44 and driving breast-cancer metastasis [E5][E6]; and in mouse cortex Mllt11 associates with stabilised microtubules and is required for neurite outgrowth and neuronal migration [E7]. High wild-type AF1q expression is an independent adverse prognostic factor in paediatric AML (8-year OS 19% vs 50%) [E8]. MLLT11 is not a dependency anywhere: Chronos mean -0.031 across 1208 lines, rank 8022 of 17,728 for KMT2A selectivity, and no dependency in either the myeloid or the B-lineage half of the KMT2A-rearranged arm [E9]. **Neither the elongation-hijack model nor the forced-oligomerisation model has any structural foothold in this protein** — and, as recorded in the fusion entry, nobody has ever tested whether the fusion transforms.
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.
Ninety residues, one annotated feature
This is worth stating flatly because the graph's models depend on it. The UniProt record for Q13015 lists, in the entire 90-residue sequence, a single feature: a nuclear export signal at aa 24-32 1. There is no bromodomain, YEATS domain, PHD finger, AT-hook, transactivation domain, coiled coil, leucine zipper, sterile-alpha motif, BTB/POZ domain, F-BAR, EH domain or any other annotated oligomerisation or chromatin module. There is no PDB entry.
Compare the other partner classes this graph covers. MLLT1/MLLT3 bring YEATS domains and the super elongation complex. MLLT10 brings a PZP module and DOT1L. EPS15 and GAS7 bring coiled coils. SEPTIN6 brings a GTPase domain plus a coiled coil. MLLT6/AF17 brings a leucine zipper. MLLT11 brings a nuclear export signal and 81 other residues that nobody has assigned a function to.
It is also a difficult protein biophysically: recombinant AF1q expressed in E. coli goes entirely into inclusion bodies and has to be refolded from denaturant, which the authors state was why its structural and biophysical properties had remained largely unexplored 5. That is the behaviour of a small, poorly folded or aggregation-prone protein, and it is consistent with the absence of any structure.
Localization: subcellular AND subnuclear, unusually well documented
This is the one saturation axis where MLLT11 is better characterised than most KMT2A partners.
Subcellular. AF1q shows pronounced karyophily — it partitions strongly into the nucleus — but is subject to constitutive nuclear export, after which it is degraded by the ubiquitin system in the centrosomal area 3. The nuclear export signal at aa 24-32 is presumably the machinery for the export half of that cycle 1. So the steady-state distribution is a dynamic nucleocytoplasmic shuttle terminating at a pericentrosomal degradation site, not a static compartment.
A second, independent degradation route. AF1Q is also degraded in lysosomes by chaperone-mediated autophagy: it carries a KFERQ-like motif recognised by HSPA8, interacts with HSPA8 and LAMP-2A, accumulates on chloroquine treatment, and falls on CMA activation by 6-aminonicotinamide or nutrient starvation 4. Two independent, actively regulated destruction pathways for a 90-residue protein is unusual and implies the cell cares a great deal about its level.
Subnuclear. Not resolved. No speckle, nucleolar, PML-body or chromatin-associated subnuclear distribution has been reported for AF1q, and none at all for the KMT2A::MLLT11 fusion protein. Said explicitly.
Cytoskeletal. In mouse cortical neurons Mllt11 is detected in varicosities and growth cones as well as the soma, and proteomics found it associates with stabilised microtubules, with Mllt11 loss affecting microtubule staining in callosal axons 7. This is the single most suggestive fact in the entry, for the reason set out in hyp-microtubule-binding-as-a-recurrent-kmt2a-partner-module.
Cell type and cell state: a T-lineage and progenitor gene
Normal expression. The founding report found AF1q mRNA highly expressed in thymus but not in peripheral lymphoid tissue, and in every leukaemic cell line tested 2. Later work describes it as highly expressed in haematopoietic progenitor cells with low expression in differentiated cells 8.
Cell state. AF1q is a lineage-decision gene in human progenitors. Forced expression promotes T- over B-cell differentiation in multipotent haematopoietic progenitors and confers increased susceptibility to Delta-like/Notch-mediated signalling; enforced expression in humanised mice fosters emergence of BM CD34+CD7+ prothymocytes, enhances thymus colonisation and accelerates intrathymic T-cell development; silencing shifts BM lymphopoiesis globally toward B lineage, hinders prothymocyte development and causes intrathymic accumulation of B cells 3.
This matters for the fusion in a specific way. KMT2A::MLLT11 is, by the 3401-patient recombinome, an almost purely myeloid fusion — 13 infant AML, 10 paediatric AML, 4 adult AML and a single infant ALL out of 28 10. So a partner whose wild-type function is to push progenitors toward T and away from B produces, as a fusion, AML. Either the fusion does not retain that function, or the KMT2A moiety overrides it. Nobody has tested which.
Epigenetics. None. No histone modification, chromatin-occupancy or transcriptome readout has been published for AF1q, for the fusion, or for a KMT2A::MLLT11 patient sample. Stated explicitly.
What AF1q actually does, when it does something
The functional literature is almost entirely about wild-type AF1q overexpressed in non-leukaemic cancers, and it converges on Wnt/TCF. AF1q binds TCF7 (TCF1) and acts as a co-factor, transcriptionally activating CD44 and multiple downstream TCF7/LEF1 targets; enhanced AF1q expression promotes breast-cancer proliferation, migration, mammosphere formation and chemo-resistance, and drives liver metastasis and lung colonisation in xenografts, with AF1q-positive cells enriched at metastatic relative to primary sites in paired patient samples 6. The interaction was subsequently mapped biophysically by NMR and analytical ultracentrifugation to the HMG domain of TCF7, residues 154-237 5.
Two cautions the entry insists on. First, all of this is about the free wild-type protein in epithelial tumours, not about the fusion in a haematopoietic cell, and the fusion retains the complete AF1q open reading frame fused to the KMT2A N-terminus 2 — a very different molecular context. Second, the prognostic association in AML is with wild-type AF1q expression level, not with the fusion, and the authors of that study said so themselves: it is not clear whether AF1q is simply a marker of a more primitive phenotype or contributes directly to leukaemogenesis 8.
Essentiality, lineage-split
MLLT11 is not required by cancer cells: DepMap Chronos mean -0.031 across 1208 lines, KMT2A-rearranged mean +0.009 against +0.017 in other leukaemia lines, and rank 8022 of 17,728 — essentially the middle of the genome — for KMT2A selectivity 9.
Because the KMT2A-rearranged DepMap panel is myeloid-enriched, the index arm was split by lineage rather than the combined figure being quoted. MLLT11 scores +0.30 SD in the myeloid half and -0.58 SD in the B-lineage half relative to the other-leukaemia arm — no dependency in either, and the reference genes run in the same panel behave as expected (MEN1 -2.29 / -2.28, KMT2A -1.48 / -1.22, both lineage-independent) 9.
An identifier failure is recorded here because it was nearly consequential: the first run of that panel used ENSG00000213445 for MLLT11, which the Open Targets target record resolves to SIPA1, a different gene. It was caught only because the script asserts the returned approvedSymbol. The correct id is ENSG00000213190, confirmed by an Ensembl REST xrefs/symbol lookup 9.
| uniprot | Q13015 |
|---|---|
| uniprot verified | Q13015 = AF1Q_HUMAN, PRIMARY gene name MLLT11, synonym AF1Q, 90 aa, Homo sapiens. Fetched from the UniProt REST API on 2026-09-19; the primary gene name and the sequence length were read back from the record rather than inferred from a synonym match. |
| length AA | 90 |
| ensembl | ENSG00000213190 |
| ensembl verified | ENSG00000213190 returned as the sole gene-level xref for symbol MLLT11 by Ensembl REST xrefs/symbol/homo_sapiens on 2026-09-19. The id ENSG00000213445, used in a first draft of this beat's DepMap panel, was REJECTED by the run's approvedSymbol assertion because Open Targets resolves it to SIPA1. |
| PDB note | NO structure of AF1q exists, in whole or in part, and none is cross-referenced from UniProt Q13015. The only biophysical work used NMR and analytical ultracentrifugation on refolded protein and deposited no coordinates. This is the shortest KMT2A partner and the least structurally characterised. |
| alphafold ID | AF-Q13015-F1 |
| domains note | This single 9-residue motif is the ENTIRE annotated feature content of the protein. No coiled coil, no leucine zipper, no chromatin-binding domain, no oligomerisation module of any kind is annotated. A KFERQ-like chaperone-mediated-autophagy motif has been mapped experimentally but its residue positions are not given in the source abstract and are therefore not entered here. |
| localization | nucleocytoplasmic shuttle: pronounced karyophily with constitutive nuclear export, terminating in ubiquitin-mediated degradation in the centrosomal area; separately degraded in lysosomes by chaperone-mediated autophagy. In neurons, present in soma, varicosities and growth cones and associated with stabilised microtubules. |
| subnuclear localization | NOT ESTABLISHED for AF1q, and not reported at all for the KMT2A::MLLT11 fusion protein. |
| epigenetic readout | NONE PUBLISHED for AF1q, for the fusion, or for any KMT2A::MLLT11 patient sample. |
| normal expression | thymus-high, peripheral-lymphoid-low by Northern blot; high in haematopoietic progenitors and low in differentiated cells; in mouse, enriched in the developing cortical plate |
| cell state function | lineage-decision gene: pushes multipotent human progenitors toward T and away from B, by raising susceptibility to Delta-like/Notch signalling |
| family | no family; no recognised homologue at the time of cloning |
PDB IDS
[]
domains
[
{
"name": "NES (nuclear export signal)",
"start": 24,
"end": 32
}
]essentiality
{
"depmap_common_essential": false,
"chronos_mean": -0.0306,
"chronos_n_lines": 1208,
"kmt2a_selectivity_rank": 8022,
"kmt2a_selectivity_of": 17728,
"kmt2a_r_mean": 0.0086,
"other_leukaemia_mean": 0.0172,
"lineage_split_z_kmt2a_myeloid": 0.3,
"lineage_split_z_kmt2a_b_lineage": -0.58,
"lineage_split_verdict": "no dependency in either half of the KMT2A-rearranged index arm",
"mouse_ko": "Mllt11 conditional knockouts exist but have been characterised only in the nervous system (cortical projection neurons, cerebellar granule cells, retina, trigeminal ganglion, social/repetitive behaviour). NO haematopoietic phenotype has been reported for any Mllt11 mouse."
}known interactors
[ "TCF7 (HMG domain, residues 154-237)", "HSPA8", "LAMP-2A", "stabilised microtubules (proteomic co-association)" ]
recombinome — the numbers behind the chart
{
"dcal_recombinome_n": 28,
"dcal_recombinome_rank": 10,
"dcal_recombinome_total_patients": 3401,
"infant_all": 1,
"infant_aml": 13,
"paediatric_all": 0,
"paediatric_aml": 10,
"adult_all": 0,
"adult_aml": 4,
"aml_pct_of_1116_aml_patients": 2.4
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": 0.0086,
"chronos_mean_other_leukaemia": 0.0172,
"difference": -0.0086,
"pan_essentiality_all_lines": -0.0306,
"selectivity_rank": 8022,
"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."
}- AF1q is degraded by two independent, pharmacologically tractable routes — chaperone-mediated autophagy and ubiquitin-dependent degradation at the centrosome — which makes 'lower the protein' look like an obvious intervention. It is not, for the fusion: the fusion protein is driven by the KMT2A promoter and its stability determinants are unknown, and chloroquine (which RAISES AF1Q by blocking lysosomal degradation) is a drug patients with leukaemia may receive for other reasons.
- Wild-type AF1q's normal function is to push progenitors toward T-lineage output. Any agent that suppressed AF1q would be expected to distort normal T-cell development, and the humanised-mouse data show silencing causes intrathymic accumulation of B cells — an immunological toxicity signal that would not be caught by a standard haematology panel.
- The prognostic association between high AF1q expression and poor survival in paediatric AML is an argument for measuring AF1q, not for targeting it: the study's own authors could not distinguish a causal role from a marker of immaturity, and the high-expression group was enriched for the least differentiated FAB subtype.
- Does AF1q self-associate? Analytical ultracentrifugation has been performed on refolded AF1q and would answer this directly, but the oligomeric state is not reported in the published abstract. If AF1q is monomeric, the forced-oligomerisation model has a genuine counterexample at 28 patients; if it self-associates, the model absorbs the case. This is a single sedimentation-velocity experiment on protein that already exists.
- Does the KMT2A::MLLT11 fusion retain AF1q's T-lineage-promoting, Notch-sensitising activity? The fusion is 27/28 myeloid, which predicts it does not — and testing that is the cleanest way to ask whether the partner contributes any of its own biology to this fusion.
- Does the AF1q NES at aa 24-32 survive in the fusion, and if so does the fusion shuttle out of the nucleus? A KMT2A fusion protein with a functional nuclear export signal would be a genuinely novel configuration and would predict a cytoplasmic pool that nobody has looked for.
- Does AF1q bind microtubules in a haematopoietic cell, as Mllt11 does in neurons? If so, MLLT11 joins GPHN as a KMT2A partner whose leukaemia-relevant module is a tubulin interaction.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Human AF1q is UniProt Q13015 (AF1Q_HUMAN), primary gene name MLLT11, synonym AF1Q, 90 amino acids, Homo sapiens; the record's only sequence feature is a nuclear export signal at aa 24-32, with no annotated domain, coiled coil, repeat, zinc finger or chromatin-binding module, and no cross-referenced PDB structure.
UniProtKB Q13015 (AF1Q_HUMAN) Protein AF1q, Homo sapiens, 90 aa · UniProt Consortium · UniProtKB 2026What this evidence cannot show
An absence of annotation is not a demonstration of absence of structure or function; a 90-residue protein with no solved structure is exactly the case where curation is least informative. The claim asserted here is about what is annotated and what structures exist, not about what the protein can do. Resolved by fetching the accession and reading back the PRIMARY gene name (MLLT11) and length (90 aa), not by trusting a gene_exact synonym match.
Evidence that argues against this (1)
- Functional modules exist in this protein that UniProt does not annotate as features: a KFERQ-like chaperone-mediated-autophagy targeting motif was mapped experimentally by amino-acid deletion mutagenesis and is recognised by HSPA8. So 'one annotated feature' should be read as a statement about curation depth, and further short linear motifs are likely to be present and unannotated. Li P et al. 2014
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Two t(1;11)(q21;q23) translocations in infants with acute myelomonocytic leukaemia fuse MLL to a novel gene AF1q on 1q21; in one patient the der(11) is an in-frame fusion of the N-terminal portion of MLL to the COMPLETE AF1q open reading frame while the der(1) gives no open reading frame; the predicted wild-type AF-1q product is a 9 kDa protein with no similarity to any other protein in the data banks; and AF1q mRNA is highly expressed in thymus but not in peripheral lymphoid tissue, while being expressed in all leukaemic cell lines tested.
A novel gene, AF1q, fused to MLL in t(1;11) (q21;q23), is specifically expressed in leukemic and immature hematopoietic cells. · Tse W, Zhu W, Chen HS, Cohen A · Blood 1995What this evidence cannot show
Two patients, 1995 methods. No DOI is registered in the PubMed record for this article (the ArticleIdList carries only the PMID), so the citation is anchored on PMID and URL rather than on a missing DOI field. 'No similarity to any other protein' is a statement about the 1995 databanks. The tissue-expression claim is a Northern-blot result on a small human tissue panel.
Evidence that argues against this (1)
- The retained-ORF architecture is not invariant: a later adult t(1;11)(q21;q23) case broke within MLL exon 10 into MLLT11 intron 1 and generated two in-frame fusion transcripts, one a normal splice product and one containing intronic sequence via a cryptic splice event, so 'the entire MLLT11 ORF is fused in frame' is the usual case and not the only one. Lee S et al. 2012
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
AF1q/MLLT11 protein shows pronounced karyophily but is subject to constitutive nuclear export followed by ubiquitin-mediated degradation in the centrosomal area; forced expression promotes T- over B-cell differentiation in multipotent haematopoietic progenitors and confers increased susceptibility to Delta-like/Notch-mediated signalling; enforced AF1q expression in humanised mice fosters emergence of BM CD34+CD7+ prothymocytes, enhances thymus colonisation and accelerates intrathymic T-cell development; and AF1q silencing shifts BM lymphopoiesis globally toward the B-cell lineage, hinders prothymocyte development, inhibits thymus colonisation and causes intrathymic accumulation of B cells.
AF1q/MLLT11 regulates the emergence of human prothymocytes through cooperative interaction with the Notch signaling pathway. · Parcelier A, Maharzi N, Delord M, Robledo-Sarmiento M, Nelson E, Belakhdar-Mekid H, et al. · Blood 2011What this evidence cannot show
Gain- and loss-of-function by forced expression and shRNA in human progenitors plus a humanised-mouse model — informative about what AF1q CAN do at non-physiological levels, not about the endogenous protein's requirement. Localisation was determined for wild-type AF1q, not for the KMT2A::MLLT11 fusion protein, and no subnuclear compartment was resolved. Read from the abstract and the PMC record header; the full text was not read in detail for this entry.
Evidence that argues against this (1)
- The lineage prediction from this work runs the wrong way for the fusion: a protein that pushes progenitors toward T and away from B should, if the fusion retained that activity, be enriched in T-lineage or B-lineage disease, yet KMT2A::MLLT11 is almost purely myeloid in the 3401-patient recombinome (27 of 28 cases AML, a single infant ALL, no T-ALL). Either the fusion does not retain the activity or the KMT2A moiety overrides it, and neither has been tested. Meyer C et al. 2023
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
AF1Q is degraded in lysosomes by chaperone-mediated autophagy: lysosomal inhibitors such as chloroquine increase AF1Q levels while CMA activators (6-aminonicotinamide, nutrient starvation) decrease them, AF1Q interacts with the core CMA components HSPA8 and LAMP-2A, knockdown of either raises and overexpression lowers AF1Q protein, and amino-acid deletion mutagenesis identified a KFERQ-like motif in AF1Q recognised by HSPA8 for CMA-dependent proteolysis.
Degradation of AF1Q by chaperone-mediated autophagy. · Li P, Ji M, Lu F, Zhang J, Li H, Cui T, et al. · Exp Cell Res 2014What this evidence cannot show
Cell-line pharmacology and knockdown, with the cell system not specified in the abstract. Read from the abstract only. The residue positions of the KFERQ-like motif are not given in the abstract and are not asserted here.
Evidence that argues against this (1)
- An independent study assigns AF1q turnover to a different machinery in a different compartment — constitutive nuclear export followed by UBIQUITIN-mediated degradation in the centrosomal area — so there are two proposed, mechanistically distinct degradation routes for this protein and no published work reconciling them or establishing which dominates in a haematopoietic progenitor. Parcelier A et al. 2011
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Recombinant AF1q overexpressed in E. coli with an N-terminal His6 tag forms inclusion bodies and had to be purified under denaturing conditions and refolded by one-step dialysis, the authors stating that the structural and biophysical properties of AF1q had remained largely unexplored because no viable method for producing recombinant protein existed; NMR and analytical ultracentrifugation measurements then showed AF1q interacts specifically with the high-mobility-group (HMG) domain of TCF7, residues 154-237, the first biophysical characterisation of that interaction.
Recombinant expression and purification of AF1q and its interaction with T-cell Factor 7. · Khan N, Park J, Dean WL, Gray RD, Tse W, Lee D, et al. · Protein Expr Purif 2020What this evidence cannot show
A methods paper. Refolded-from-inclusion-bodies protein is not guaranteed to be natively folded, and no structure was deposited. Crucially, the abstract does NOT report AF1q's own oligomeric state even though analytical ultracentrifugation is the assay that would give it — so this entry does not claim AF1q is monomeric, only that no self-association has been reported.
Evidence that argues against this (1)
- The contrasting case in this beat is EPS15/GAS7, where the transforming module was defined by demonstrating self-association and then showing that synthetic dimerisation modules substitute for it. Nothing equivalent has ever been attempted for AF1q, so its absence from the oligomerisation literature reflects an experiment not done rather than a negative result. So CW et al. 2003
- E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
AF1q binds T-cell factor 7 (TCF7) in the Wnt signalling pathway and transcriptionally activates CD44 and multiple downstream TCF7/LEF1 targets; enhanced AF1q expression promotes breast-cancer cell proliferation, migration, mammosphere formation and chemo-resistance, and in xenografts promotes liver metastasis and lung colonisation; in a 63-patient breast-cancer cohort, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall, disease-free and brain-metastasis-free survival, and paired primary/metastatic samples showed AF1q-positive cells becoming dominant at metastatic sites.
AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis. · Park J, Schlederer M, Schreiber M, Ice R, Merkel O, Bilban M, et al. · Oncotarget 2015What this evidence cannot show
Breast-cancer epithelial cells and xenografts, not haematopoietic cells, and about the free wild-type protein, not about the KMT2A::MLLT11 fusion. The clinical component is a 63-patient retrospective immunohistochemistry cohort. Oncotarget's post-2015 indexing problems are a known concern about the venue and are noted rather than used to dismiss the result, which is supported by an independent biophysical mapping of the same interaction.
Evidence that argues against this (1)
- TCF7 itself is not a KMT2A-selective dependency in the DepMap panel used throughout this project — genome-wide KMT2A-selectivity rank 10,975 of 17,728, KMT2A-rearranged mean -0.182 against -0.196 in other leukaemia lines, and -0.09 / +0.09 SD in the myeloid and B-lineage halves of the index arm — so if the AF1q/TCF7/CD44 axis operated in KMT2A-rearranged leukaemia it leaves no dependency signature there. Broad Institute DepMap; Open Targets Platform; lineage split run by this project 2026
- E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Mllt11 expression is exclusive to developing neurons and enriched in the developing cortical plate; in cultured primary cortical neurons Mllt11 is detected in varicosities and growth cones as well as the soma; conditional loss and gain of function show it is required for neuritogenesis and proper migration of upper-layer cortical projection neurons; and proteomic analysis revealed Mllt11 associates with stabilised microtubules, with Mllt11 loss affecting microtubule staining in callosal axons.
Mllt11 Regulates Migration and Neurite Outgrowth of Cortical Projection Neurons during Development. · Stanton-Turcotte D, Hsu K, Moore SA, Yamada M, Fawcett JP, Iulianella A · J Neurosci 2022What this evidence cannot show
Mouse developing neocortex. The microtubule association is a proteomic co-association plus an immunostaining phenotype, not a demonstrated direct binding, and no binding site or affinity is reported. Nothing in this paper concerns haematopoietic cells or the fusion; it is used here for the biochemical activity of the protein, not for a leukaemia claim.
Evidence that argues against this (1)
- 'Expression exclusive to developing neurons' directly contradicts the haematopoietic literature on the same gene, which reports AF1q mRNA highly expressed in thymus and in every leukaemic cell line tested, and the protein highly expressed in haematopoietic progenitor cells with low expression in differentiated cells. The two bodies of work are on mouse developing brain and human haematopoietic tissue respectively; the exclusivity claim should be read as scoped to the developing CNS. Tse W et al. 1995
- E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In 64 paediatric AML patients treated on Children's Cancer Group trial CCG-2891, AF1q expression by RT-PCR varied from 0- to 154-fold relative to normal marrow; increasing expression was associated with worsening survival (hazard ratio 1.02 per fold increase, P = .032); patients in the top expression tertile had a higher predominance of FAB M1 (43% vs 9%, P = .003); and 8-year overall survival was 19% in the high-AF1q group versus 50% in the low-AF1q group (P = .01), with high AF1q expression adverse in both univariate and multivariate models.
Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia. · Tse W, Meshinchi S, Alonzo TA, Stirewalt DL, Gerbing RB, Woods WG, et al. · Blood 2004What this evidence cannot show
n = 64, a tertile split chosen post hoc, and semi-quantitative RT-PCR as the assay. This is about WILD-TYPE AF1q expression level in unselected paediatric AML, NOT about KMT2A::MLLT11 fusion-positive disease, and must not be read as prognostic information for the fusion. The authors state explicitly that it is not clear whether AF1q is simply a marker of a more primitive phenotype or contributes directly to leukaemogenesis.
Evidence that argues against this (1)
- An expression-prognosis association of this shape is exactly what a stemness or immaturity marker produces without any causal role, and the confound is visible inside the study itself: the high-AF1q group was enriched for FAB M1, the least differentiated myeloid morphology. The same caution is reinforced by AF1q being a Notch-responsive progenitor gene whose normal expression is highest in immature cells. Parcelier A et al. 2011
- E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
MLLT11 is not a dependency in any leukaemia context measured: DepMap Chronos mean gene effect -0.0306 across 1208 lines, KMT2A-rearranged mean +0.0086 versus +0.0172 in other leukaemia lines, rank 8022 of 17,728 (45.3rd percentile) for KMT2A selectivity; and when the KMT2A-rearranged index arm is split by lineage, MLLT11 scores +0.30 SD in the 8-line myeloid half and -0.58 SD in the 5-line B-lineage half of the other-leukaemia distribution. In the same lineage-split run, MEN1 scores -2.29 / -2.28 and KMT2A -1.48 / -1.22, both lineage-independent, confirming the panel resolves real dependencies. The Ensembl identifier ENSG00000213445 was rejected by the run's symbol assertion because it resolves to SIPA1, not MLLT11; the correct id is ENSG00000213190.
DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API: genome-wide KMT2A-selectivity scan (analyses/depmap-kmt2a-selective-scan-full/results.json) plus the lineage-split re-analysis of the deferred KMT2A partners run for this beat (analyses/depmap-deferred-partners-lineage-split/); Ensembl identifiers confirmed by Ensembl REST xrefs/symbol · Broad Institute DepMap; Open Targets Platform; Ensembl; lineage split run by this project · Database and derived analysis 2026What this evidence cannot show
Decisive limitation: no KMT2A::MLLT11 cell line exists in the DepMap panel, so this measures wild-type MLLT11 in leukaemias driven by other partners and cannot address whether the fusion creates a dependency. The lineage split rests on 8 myeloid and 5 B-lineage lines, so one line moves a mean. Chronos scores near zero are where noise dominates. DepMap release version is not stated by the API.
Evidence that argues against this (1)
- A CRISPR null for the wild-type partner gene is weak evidence about a fusion in general, and this project has the clearest demonstration of that: Sept6-null mice develop normally AND the MLL-SEPT6 disease is unchanged on the null background, yet the SEPT6 coiled coil is individually required for transformation when present in the fusion. Partner-gene dispensability and fusion-module necessity are independent facts. Ono R et al. 2005
- E10established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In Table 1 of the 3401-patient 2023 KMT2A recombinome, MLLT11 is the 10th most frequent direct translocation partner with 28 patients, distributed as 1 infant ALL, 13 infant AML, 0 paediatric ALL, 10 paediatric AML, 0 adult ALL, 4 adult AML and none in the other or unclassified categories; the text independently reports MLLT11 as n = 27 (2.4%) among the 1116 AML patients.
The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, Burmeister T, Gröger D, Sutton R, et al. · Leukemia 2023What this evidence cannot show
Read directly from the Europe PMC full-text XML of PMC10169636 for this entry (Table 1 header: direct TPG, then Infant/Pediatric/Adult/not-age-classified each split ALL/AML/other, then Total), not taken from a prior entry's summary. This is a referral cohort accrued 2003-2022 from 20 countries and the counts are ascertainment-weighted, not population incidence.
Evidence that argues against this (1)
- The recombinome under-counts partners that are cytogenetically cryptic or that require transcript typing to detect, and the same table proves it can be internally inconsistent: the EPS15 row totals 55 patients while the spliced-fusion paragraph in the same paper refers to 'EPS15 (12 out of 51 cases)'. Treat every count here as a floor with a few units of uncertainty. Meyer C et al. 2023
- ← part ofKMT2A::MLLT11 (MLL-AF1q), t(1;11)(q21;q23) — 28 patients, and not one functional experiment
the complete 90-residue MLLT11 open reading frame, including the NES at aa 24-32
- ← fuses withKMT2A / MLL1 — the gene that breaks
t(1;11)(q21;q23); 28 patients, rank 10 of all direct KMT2A partners
deferred by that enumeration at 28 patients / 14 records as the sharpest remaining challenge; written here
menin dependence predicted from the retained KMT2A N-terminus but never tested for this fusion
Mllt11 associates with stabilised microtubules by proteomics in cortical neurons