KMT2A::AFF1 needs a developmental window and a lymphoid-committed cell — the cell type is a condition of transformation, not a consequence of it
also called MLL-AF4 developmental window · AFF1 cell of origin
The fusion at the centre of this project cannot turn just any blood cell into leukaemia. It works during a particular stretch of development, and its full cancer-causing power only appears once the cell has committed to becoming a B cell.
The same thing, for a scientist
Two murine results place KMT2A::AFF1 transformation in a cell context rather than letting the fusion define one. Mll-AF4 confers enhanced self-renewal and lymphoid potential only during a RESTRICTED WINDOW in development [E1], and the FULL transforming capacity of MLL-Af4 is interlinked with LYMPHOID LINEAGE COMMITMENT [E2]. A human arm points the same way from the negative side: the reciprocal AF4-MLL transiently augments multilineage engraftment in cord-blood CD34+ cells but is NOT sufficient to initiate leukaemia [E3]. A 2025 model then shows what the permissive combination produces: a distinct CD24-positive pre-leukaemic state [E4].
The dependency screen cannot see any of this, and says so loudly
AFF1 is the 3' partner of the index fusion and sits at degree 54 in this graph. In DepMap it is the least essential gene in the entire worklist: depleted below -0.5 in 0.2% of 1,258 lines, mean gene effect +0.068, and -0.257 across eleven KMT2A-rearranged lines including the four KMT2A::AFF1 lines themselves 5.
That number must not be read as 'AFF1 is dispensable'. The library cuts the whole AFF1 locus, so the wild-type allele and the fusion allele go together, and the transforming moiety is the 3' AFF1 portion retained in the fusion. A gene-keyed dependency screen is the wrong instrument for a 3' fusion partner, and the striking zero is a property of the instrument. The right instrument is a degron on the fusion allele; this graph already carries concept-degron-on-the-fusion-allele-versus-on-an-overexpressed-construct on the point.
What 'cell type' means for this fusion, stated carefully
The reading this evidence supports is not 'the cell of origin is a pro-B cell'. It is that transformation requires a coincidence: a fusion, a developmental window, and enough lineage commitment for the fusion's programme to act on. Remove any one and the result is a pre-leukaemic expansion rather than leukaemia 13.
That is why this entry links to cell-state-neonatal-window-of-transformability and to cell-type-fetal-preprob-cd10-negative rather than to a single compartment.
| gene | gene-aff1 |
|---|---|
| uniprot | P51825 |
| evidence class | 3 |
cell type
{
"transformation_requires": [
"a restricted developmental window",
"lymphoid lineage commitment"
],
"insufficient_alone": "reciprocal AF4-MLL in human cord blood CD34+"
}cell state
{
"maintains": [
"cell-state-differentiation-block",
"cell-state-fetal-program-retention",
"cell-state-stem-like-self-renewal"
],
"creates": "cell-state-cd24-positive-preleukaemic-kmt2a-aff1"
}depmap
{
"pct_all_lines_depleted": 0.2,
"mean_all_lines": 0.068,
"mean_kmt2ar": -0.257,
"instrument_mismatch": "gene-keyed CRISPR cannot test a 3' fusion partner"
}- If transformation needs lineage commitment, a therapy that de-differentiates blasts could move them out of the state the fusion depends on - or into a more primitive, more drug-tolerant one. The direction is not predictable from this evidence.
- The near-zero DepMap effect for AFF1 will be quoted as evidence that the 3' partner is not a target; it is evidence about the assay.
- Everything load-bearing here is murine, and murine models of this specific fusion have repeatedly failed to reproduce the human infant B-lineage disease.
- Does KMT2A::AFF1 require lymphoid commitment in HUMAN cells, or is that a property of the murine models? The human cord-blood work tests the reciprocal, not the fusion.
- Is the CD24-positive pre-leukaemic state the product of the restricted window, or a separate phenomenon? The two literatures have not been joined.
- What does an allele-selective degron on KMT2A::AFF1 do in SEM, SEMK2, RS4;11 and MV4-11, where whole-gene CRISPR does nothing?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mice, Mll-AF4 confers enhanced self-renewal and lymphoid potential only during a restricted window in development.
Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development. · Barrett NA, Malouf C, et al. · Cell reports 2016What this evidence cannot show
Murine Mll-AF4 (brief rule 73): not human, and mouse models of this fusion are notoriously poor at producing the human B-lineage disease. Abstract read in this beat.
Evidence that argues against this (1)
- ENHANCED SELF-RENEWAL IS NOT TRANSFORMATION, and a knock-in mouse is not an infant. Mll-AF4 conferring self-renewal and lymphoid potential in a restricted window is a change in progenitor behaviour; leukaemia in these models is famously slow, incompletely penetrant or absent, which is itself the long-standing difficulty with modelling KMT2A::AFF1. An entry titled 'needs a window' rests on the window being necessary for TRANSFORMATION, which this does not show. Oncofusion knowledge graph (internal entry) 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment.
The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment. · Lin S, Luo RT, et al. · Blood 2017What this evidence cannot show
Murine MLL-Af4 knock-in (brief rule 73). Abstract read in this beat; the strength of the lineage-commitment requirement is the authors' framing and the full text was not opened here.
Evidence that argues against this (1)
- The lymphoid-commitment requirement is in tension with the human data: the reciprocal AF4-MLL in cord-blood CD34+ cells augments MULTILINEAGE engraftment rather than lymphoid specifically, and does not initiate leukaemia at all. Whether lymphoid commitment is required, permissive or merely correlated has not been separated in human cells. Prieto C et al. 2017
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In human cord-blood CD34+ cells, the AF4-MLL reciprocal fusion transiently augments multilineage haematopoietic engraftment but is not sufficient to initiate leukaemia.
The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34(+) cells. · Prieto C, Marschalek R, et al. · Oncotarget 2017What this evidence cannot show
Human cord blood, which is the right species and close to the right cell type, but the construct is the RECIPROCAL AF4-MLL rather than KMT2A::AFF1, so it is evidence about the reciprocal and not directly about the index fusion. Abstract read in this beat.
Evidence that argues against this (1)
- THIS IS THE RECIPROCAL FUSION, NOT KMT2A::AFF1, AND THE EFFECT IS TRANSIENT. AF4-MLL is the der(4) product and is present in only a subset of patients; using it to argue about KMT2A::AFF1's requirements assumes the two are interchangeable, which this graph elsewhere treats as an open question. 'Transiently augments multilineage haematopoietic potential' in cord blood is also several steps short of a lymphoid-commitment requirement. Oncofusion knowledge graph (internal entry) 2026
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Ontogeny-specific induction of KMT2A::AFF1 drives development of a distinct CD24-positive pre-leukaemic state.
Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state. · Calderón AS, Ghazanfari R, et al. · Leukemia 2025What this evidence cannot show
2025 report in Leukemia; abstract read in this beat. An induction model, not patient material.
Evidence that argues against this (1)
- PRE-LEUKAEMIC AGAIN, AND CITED IN TWO ENTRIES FOR TWO DIFFERENT CONCLUSIONS. The same CD24-positive result supports the window claim in one entry and the lymphoid-commitment claim here. It can carry one of those or neither; a single murine pre-leukaemic phenotype cannot independently establish two necessary conditions. Oncofusion knowledge graph (internal entry) 2026
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
In DepMap fetched 2026-09-20, AFF1 is depleted below -0.5 in 0.2% of 1,258 screened lines - the lowest fraction in this beat's worklist - with a mean of +0.068 overall and -0.257 across eleven KMT2A-rearranged lines.
Open Targets Platform - DepMap CRISPR gene essentiality (depMapEssentiality), queried by Ensembl gene id 2026-09-20 · Open Targets Platform GraphQL API 2026What this evidence cannot show
Whole-gene CRISPR cuts wild-type and fusion alleles together, so this is not a test of the fusion's 3' moiety. Four of the eleven KMT2A-rearranged lines carry KMT2A::AFF1. Cancer lines in culture.
Evidence that argues against this (1)
- A DEPMAP NULL FOR WILD-TYPE AFF1 SAYS LITTLE ABOUT THE FUSION, AND CUTS BOTH WAYS. AFF1 being depleted below -0.5 in 0.2% of 1,258 lines shows the wild-type gene is broadly dispensable; the screened lines are overwhelmingly not KMT2A::AFF1, and CRISPR targeting of AFF1 hits both the fusion and the wild-type allele in lines that do carry it. If anything this argues the requirement is fusion-specific rather than AFF1-specific, which is a different claim from the one the item is placed under. Oncofusion knowledge graph (internal entry) 2026
the cell-context dossier for this gene
- supports →The neonatal window — the state in which an MLL fusion can transform, bounded at both ends
the restricted developmental window in which Mll-AF4 confers self-renewal and lymphoid potential
- related to →The CD24-positive pre-leukaemic state — what the index fusion makes before it makes leukaemia
what the permissive combination produces: a CD24-positive pre-leukaemic state
lymphoid commitment is required for full transforming capacity, which points at a committed B-lineage precursor rather than a stem cell