The neonatal window — the state in which an MLL fusion can transform, bounded at both ends
also called neonatal permissive window · age-dependent transformability · window of transformation
There is a period around birth when blood cells can be turned into leukaemia by an MLL fusion much more easily than before or after. The window is a property of the cell's condition and of its surroundings, not of the fusion.
The same thing, for a scientist
Three murine studies converge on a time-bounded permissive state rather than on a cell type. The efficiency of MLL-ENL-driven leukaemia initiation changes with age and PEAKS during neonatal development [E1]; the developmental stage of the haematopoietic NICHE, not only of the cell, regulates which lineage the resulting leukaemia takes [E2]; and adult haematopoietic stem cells are INTRINSICALLY PROTECTED against MLL-ENL transformation [E3]. A fourth result names a gene that sustains the state: SKIDA1 sustains MLL::ENL-expressing haematopoietic progenitors specifically during neonatal stages and promotes B-lineage priming [E4]. The state is bounded at the late end by adult-HSC protection and at the early end by a fetal protective programme that depends on MLL3 [E5].
Why this is a STATE and not a cell type
The obvious reading of infant leukaemia is that a particular cell type — a fetal pre-pro-B, an LMPP — is the cell of origin. The evidence assembled here says something different and more useful: the same compartment is permissive at one age and refractory at another 13, and the NICHE contributes independently of the cell 2. That makes it a condition the cell is in, which is why this graph files it under cell_state and links it to cell types rather than replacing them.
It also means an experiment that transplants a sorted population into an adult recipient has changed the variable it meant to hold fixed.
Bounded at both ends, which is the part that is easy to miss
The neonatal peak is usually told as 'infants are vulnerable'. Two results bound it. Adult HSCs resist MLL-ENL transformation intrinsically — a cell-autonomous block, not a niche effect 3. And fetal context conveys heritable protection against MLL-rearranged leukaemia in a manner dependent on MLL3 5, so the fetal programme is not uniformly permissive either.
That cuts directly against reading cell-state-fetal-program-retention as straightforwardly pro-leukaemic, and the two entries should be read together.
What this predicts that is checkable
If transformability is a bounded window rather than a cell identity, then a human system that induces KMT2A::AFF1 at different ontogenetic stages in the SAME starting material should produce different pre-leukaemic states, not merely different efficiencies. That experiment has now been done and it does: ontogeny-specific induction produces a distinct CD24-positive pre-leukaemic state 6.
| state definition | A time-bounded permissive condition, peaking neonatally, in which a KMT2A fusion can transform haematopoietic progenitors; bounded above by intrinsic adult-HSC resistance and below by an MLL3-dependent fetal protective programme |
|---|---|
| location | fetal liver and neonatal bone marrow; the niche contributes independently of the cell |
markers
[ "age of the host at induction", "B-lineage priming in the transformed progenitor", "CD24 in the KMT2A::AFF1 pre-leukaemic state" ]
genes named in the state
[ "MLLT1", "SKIDA1", "AFF1", "MLL3/KMT2C (protective)" ]
atlas refs — the numbers behind the chart
[
{
"label": "age-dependent MLL-ENL initiation efficiency",
"pmid": "31405949",
"title": "The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.",
"authors": "Okeyo-Owuor T, Li Y, Patel RM, et al.",
"venue": "Blood Adv",
"year": 2019,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
},
{
"label": "niche developmental stage sets lineage",
"pmid": "30728174",
"title": "The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia.",
"authors": "Rowe RG, Lummertz da Rocha E, Sousa P, et al.",
"venue": "J Exp Med",
"year": 2019,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
},
{
"label": "adult HSC intrinsic protection",
"pmid": "25456127",
"title": "Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.",
"authors": "Ugale A, Norddahl GL, Wahlestedt M, et al.",
"venue": "Cell Rep",
"year": 2014,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}
]relation to existing entries
{
"cell-state-fetal-program-retention": "overlapping but not identical; this entry bounds the fetal programme rather than assuming it is permissive",
"cell-type-fetal-liver-hsc": "the compartment the window opens in",
"cell-type-lmpp": "the compartment most often nominated as the transforming target"
}- A therapy aimed at a state that only exists around birth cannot be given to the patients who present with the disease — by diagnosis the window has closed, and the target may be gone with it.
- If transformability is a window, then a preleukaemic clone detected at birth carries a risk that DECLINES with age, which argues against, not for, early intervention in most carriers.
- Model systems that induce the fusion in adult mice are testing a refractory state and will systematically understate transforming potency.
- Is the window a property of the cell, the niche, or both? No experiment yet holds one fixed while moving the other.
- Does the same window exist for KMT2A::AFF1 as for KMT2A::MLLT1? Almost all the age-dependence work is MLL-ENL.
- Is the MLL3-dependent fetal protection the same mechanism as adult-HSC intrinsic protection, or two different blocks at the two ends of the window?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mice, the efficiency of MLL-ENL-driven leukaemia initiation changes with age and peaks during neonatal development.
The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development. · Okeyo-Owuor T, Li Y, et al. · Blood advances 2019What this evidence cannot show
Murine MLL-ENL, i.e. KMT2A::MLLT1 (brief rule 73): not human, and not the index KMT2A::AFF1. Abstract read in this beat.
Evidence that argues against this (1)
- THE WRONG FUSION AND A RATE RATHER THAN A BOUNDARY. MLL-ENL is not KMT2A::AFF1, and 'initiation efficiency peaks during neonatal development' describes a rate that varies with age - it does not establish a window with edges, which is what this entry's title claims. A smoothly varying efficiency and a bounded permissive state are different models and this result does not separate them. Oncofusion knowledge graph (internal entry) 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mice, the developmental stage of the haematopoietic niche regulates the lineage that MLL-rearranged leukaemia takes.
The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia. · Rowe RG, Lummertz da Rocha E, et al. · The Journal of experimental medicine 2019What this evidence cannot show
Murine. Establishes a niche contribution but does not separate niche from cell-intrinsic age in a single experiment. Abstract read in this beat.
Evidence that argues against this (1)
- NICHE AND CELL-INTRINSIC STAGE ARE NOT SEPARATED HERE. Showing that the developmental stage of the haematopoietic niche regulates the lineage of MLL-rearranged leukaemia establishes that something about developmental context matters; it does not locate that something in the niche as against the progenitor, because the two change together in any ontogeny experiment. A transplant of staged progenitors into a fixed-age niche, and the converse, is what would separate them. Oncofusion knowledge graph (internal entry) 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Adult murine haematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.
Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation. · Ugale A, Norddahl GL, et al. · Cell reports 2014What this evidence cannot show
Murine, MLL-ENL. A negative result about the compartment the field's default assumption favours; that is what makes it load-bearing here. Abstract read in this beat.
Evidence that argues against this (1)
- The window is not the only determinant of the target cell. HSC-independent progenitors are susceptible to Mll-Af9-induced transformation (PMID 37509285), which means susceptibility is distributed across compartments rather than confined to a single window-defined cell, and the neonatal peak could be a quantitative rather than a qualitative boundary. Barone C et al. 2023
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In mice, SKIDA1 sustains MLL::ENL-expressing haematopoietic progenitors during neonatal stages and promotes B-lineage priming.
SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming. · Mendoza-Castrejon J, Yang W, et al. · Blood neoplasia 2026What this evidence cannot show
Murine; 2026 report in Blood Neoplasia. Abstract read in this beat. Names a gene for the state but does not show that removing it closes the window.
Evidence that argues against this (1)
- ONE GENE IN ONE MURINE MODEL OF THE WRONG FUSION. SKIDA1 sustaining MLL::ENL progenitors neonatally is a single-gene requirement in a single system, and a factor required during a developmental stage is not evidence that the stage is a window - it is equally consistent with SKIDA1 being expressed in that stage for unrelated reasons. Oncofusion knowledge graph (internal entry) 2026
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.preprint
Fetal context conveys heritable protection against MLL-rearranged leukaemia in a manner dependent on MLL3.
Fetal context conveys heritable protection against MLL-rearranged leukemia that depends on MLL3. · Mendoza-Castrejon J, Yang W, et al. · bioRxiv : the preprint server for biology 2025What this evidence cannot show
bioRxiv PREPRINT, not peer reviewed at the version cited (a journal version PMID 41032751 also exists and was seen in the same search). Murine. MLL3 here is KMT2C, not KMT2B or KMT2D.
Evidence that argues against this (1)
- THIS RESULT COMPLICATES THE WINDOW MODEL RATHER THAN SUPPORTING IT, AND SHOULD BE READ THAT WAY. 'Fetal context conveys heritable PROTECTION' places the fetal period on the resistant side, while the human evidence places the INITIATING event in utero - twin concordance and neonatal blood-spot backtracking both date the fusion before birth. A model in which the fetal state protects and the neonatal state permits has to explain why the human lesion arises in the protected window. The MLL3 dependence also makes this a two-gene result rather than a property of ontogeny. Oncofusion knowledge graph (internal entry) 2026
- E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Ontogeny-specific induction of the KMT2A::AFF1 fusion 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. The index fusion, which most of the rest of this entry is not.
Evidence that argues against this (1)
- PRE-LEUKAEMIC IS NOT LEUKAEMIC, AND THAT IS THE WHOLE DISTANCE THIS ENTRY NEEDS TO CROSS. A CD24-positive pre-leukaemic state induced ontogeny-specifically is the closest result here to the index fusion - it is genuinely KMT2A::AFF1 - but a pre-leukaemic state that never becomes leukaemia would produce the same observation, and the window claim is about transformation. It is also murine. Oncofusion knowledge graph (internal entry) 2026
MLL-ENL initiation efficiency peaks neonatally and adult HSCs are intrinsically protected
bounds the fetal programme rather than assuming it is permissive: fetal context conveys MLL3-dependent heritable PROTECTION
the compartment the window opens in
the compartment most often nominated as the transforming target
adult HSCs are intrinsically PROTECTED against MLL-ENL transformation, which closes the window at the late end
the clinical counterpart of a neonatal permissive window
- ← part ofThe CD24-positive pre-leukaemic state — what the index fusion makes before it makes leukaemia
the state the permissive window produces when the fusion is induced inside it
the restricted developmental window in which Mll-AF4 confers self-renewal and lymphoid potential
MLL-ENL is the fusion in which the neonatal window was measured
another ontogeny-restricted permissive compartment; whether the two windows are the same window is open
the TdT gene SWITCHES ON in the first week after birth in mice, so a fetal or neonatal lymphoid progenitor is TdT-low by developmental schedule - which would produce TdT-negative infant B-ALL (median age 1.4 years, 100% KMT2A-rearranged) without the fusion repressing anything (PMIDs 8356452, 34148065)