The age of the marrow, not only the age of the cell, decides whether MLL-rearranged leukaemia comes out myeloid or lymphoid
also called heterochronic niche transplantation · age-specific leukaemia phenotype · neonatal versus adult microenvironment
Put the same leukaemia into a newborn mouse and into an adult mouse and you get different diseases: in the newborn it acquires B-cell character, in the adult it stays myeloid. The difference is not in the leukaemia cell at all — it is in the surrounding marrow, and one of the molecules responsible has been identified.
The same thing, for a scientist
Heterochronic transplantation of MLL/KMT2A-translocation-driven leukaemia separated the contribution of the host microenvironment from that of the leukaemic cell. **MLL-AF9 leukaemia cells sustained a myeloid phenotype in the adult microenvironment but generated mixed early B-cell/myeloid leukaemia in the neonatal microenvironment**; in **MLL-ENL** leukaemia the neonatal microenvironment potentiated B-lymphoid differentiation relative to the adult. The mechanism identified is **Ccl5 elaborated from adult marrow stroma, which inhibits B-lymphoid differentiation of leukaemia cells** [E1]. This is the most consequential niche result in the graph for an infant-leukaemia project, because it means the lineage of KMT2A-rearranged leukaemia - the property that defines infant ALL against paediatric AML and that the lineage-switch literature treats as cell-intrinsic plasticity - is partly set by **where the cell is**, on a variable (host age) that no cell-autonomous model contains. It sits directly alongside `mechanism-lineage-switch-kmt2a` and `cell-state-fetal-program-retention`, both of which explain lineage from inside the cell.
The experiment
Heterochronic transplantation means putting cells from one age of animal into a host of a different age, so that the cell's developmental stage and the environment's developmental stage can be varied independently. Rowe and colleagues did this with leukaemia rather than with normal haematopoiesis.
The result: the same MLL-AF9 leukaemia gave a myeloid disease in an adult host and a mixed early B-cell/myeloid disease in a neonatal host. MLL-ENL leukaemia showed the same direction — more B-lymphoid differentiation in the neonate 1.
The mediator they identify runs the other way from what one might expect: it is not a neonatal factor that promotes B-lineage, it is an adult factor that suppresses it. Ccl5 from adult marrow stroma inhibits B-lymphoid differentiation of leukaemia cells 1. The neonatal niche is permissive by absence.
Why this is the most important niche finding for this project
Infant KMT2A-rearranged leukaemia is overwhelmingly B-lymphoid; paediatric and adult KMT2A-rearranged leukaemia is far more often myeloid; and mixed-phenotype and lineage-switching cases are frequent enough that this graph has three separate entries about them (mechanism-kmt2a-mpal-mixed-phenotype, mechanism-lineage-switch-kmt2a, cell-state-fetal-program-retention). Every one of those explanations is cell-intrinsic: the cell of origin, the retained fetal programme, the plasticity of the epigenetic state.
1 adds a variable none of them contains. The age of the host marrow changes the lineage output of a fixed leukaemic genotype. Three consequences follow for this graph:
- The age distribution of phenotype may be partly environmental. That infant KMT2A-rearranged leukaemia is lymphoid and adult is myeloid has always been read as evidence about the cell of origin. It is also consistent with a fixed cell of origin in different marrows.
- Lineage switch on therapy may have a niche component. Lineage switch in this disease is usually attributed to selection or reprogramming under pressure. If adult-type stromal CCL5 suppresses B-lineage, then anything that changes stromal CCL5 - including inflammation, chemotherapy or the leukaemia's own remodelling of the stroma - is a candidate contributor. This graph should not assert that; it should test it.
- Every mouse model of infant leukaemia run in an adult host is answering a question about adult marrow. Xenografts are conventionally done in adult immunodeficient mice. If the host niche sets lineage, then the standard model systematically misrepresents the disease it is modelling, and the fix - neonatal transplantation - is available and rarely used.
| mechanism class | developmental-stage-dependent microenvironmental control of lineage |
|---|---|
| design | heterochronic transplantation (leukaemia cells into neonatal versus adult hosts) |
| mediator | CCL5 from adult marrow stroma inhibits B-lymphoid differentiation of leukaemia cells |
| opposing result | fetal MLL::ENL lymphomyeloid multipotent progenitors are intrinsically programmed towards a lymphoid fate but give rise to MYELOID leukaemia in vivo (PMID 38555405), so the environmental contribution is not consistent in direction across the two studies |
| adhesion interface not yet written | the same study reports differential regulation of Igf2 bioavailability and of the VLA-4 dimer and its ligandome upon leukaemia initiation; the VLA-4/VCAM-1 x KMT2A PubMed intersection is 2 records and this beat has no adhesion entry |
results
[
{
"driver": "MLL-AF9",
"adult_host": "myeloid phenotype sustained",
"neonatal_host": "mixed early B cell / myeloid leukaemia"
},
{
"driver": "MLL-ENL",
"adult_host": "less B-lymphoid",
"neonatal_host": "potentiated B-lymphoid differentiation"
}
]implications for this graph
[ "the lymphoid phenotype of infant KMT2A-rearranged leukaemia may be partly environmental rather than wholly cell-of-origin", "lineage switch under therapy has an untested stromal candidate mechanism", "adult-host xenografts of infant leukaemia are modelling an adult niche" ]
untested in
[ "KMT2A::AFF1", "human tissue", "infant-aged xenograft hosts" ]
related entries
[ "mechanism-lineage-switch-kmt2a", "cell-state-fetal-program-retention", "cell-type-fetal-liver-hsc", "mechanism-kmt2a-mpal-mixed-phenotype" ]
atlas refs
[
{
"label": "Heterochronic transplantation: niche age sets MLL-rearranged leukaemia 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."
}
]- If the niche sets lineage, then an intervention that changes the stroma could change the lineage of the disease it is treating - and lineage switch to myeloid is a recognised escape route from B-cell-directed immunotherapy in exactly this genotype.
- CCL5 is a broadly acting inflammatory chemokine; manipulating it therapeutically in an infant would have immunological consequences far beyond the marrow.
- This result undermines the transferability of preclinical data in both directions: adult-host results may not describe infant disease, and infant-host results would not describe the older children who also carry these fusions.
- Does CCL5 blockade in an adult host reproduce the neonatal lineage phenotype? That is the experiment that would turn an association between host age and lineage into a mechanism, and the abstract does not report it.
- Does the effect hold for KMT2A::AFF1, the fusion that actually causes infant ALL? Both drivers tested are myeloid-associated fusions.
- Is stromal CCL5 measurable in human marrow, and does it differ between infants and older children with KMT2A-rearranged disease? A trephine immunoassay would test the human relevance directly.
- Do lineage switches on therapy correlate with changes in stromal CCL5, given that leukaemia remodels the mesenchymal compartment and chemotherapy does too?
- Should this project's xenografts be done in neonatal hosts? If host age sets lineage, the standard adult NSG xenograft is a model of the wrong microenvironment.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Heterochronic transplantation of leukaemia driven by MLL/KMT2A translocations shows that the age of the haematopoietic microenvironment determines leukaemia lineage: MLL-AF9 leukaemia cells sustained a myeloid phenotype in the adult microenvironment whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukaemia, and in MLL-ENL leukaemia the neonatal microenvironment potentiated B-lymphoid differentiation compared with the adult; Ccl5 elaborated from adult marrow stroma inhibits B-lymphoid differentiation of leukaemia cells.
The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia · Rowe RG, Lummertz da Rocha E, Sousa P, Missios P, Morse M, Marion W, Yermalovich A, Barragan J, et al. · Journal of Experimental Medicine 2019What this evidence cannot show
Mouse transplantation with murine MLL-AF9 and MLL-ENL; neither fusion is KMT2A::AFF1, the fusion that dominates infant ALL, and no human or KMT2A::AFF1 arm is reported in the abstract. 'Neonatal' mouse marrow is not human infant marrow, and the mouse switches from fetal to adult haematopoietic programmes on a timetable that is not the human one. CCL5 is identified as a mechanism of the age effect, not necessarily the only one, and the abstract does not report whether CCL5 blockade in an adult host reproduces the neonatal phenotype. Read: abstract only.
Evidence that argues against this (1)
- The environment does not simply override the cell, and the clearest demonstration runs the OPPOSITE way to the heterochronic result: fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors are intrinsically programmed towards a LYMPHOID fate yet give rise to MYELOID leukaemia in vivo. So a fetal-origin cell with a lymphoid intrinsic programme produced myeloid disease, where the heterochronic experiment had a neonatal environment producing B-lymphoid character from a myeloid leukaemia. Both papers conclude that intra- and extracellular factors interact; neither establishes which dominates, and the direction of the environmental contribution is not consistent between them. The same study also reports differential regulation of Igf2 bioavailability and of the VLA-4 dimer and its ligandome as leukaemia initiates, which is a second, adhesion-based niche interface this beat has no entry for. Read: abstract only. Jassinskaja M et al. 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Compartment-specific deletion of Cxcl12 shows that early lymphoid progenitors depend on osteoblast-derived CXCL12 and occupy an endosteal niche distinct from the perivascular niche occupied by HSCs, establishing that the marrow niche is lineage-partitioned and not a single microenvironment.
Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches · Ding L, Morrison SJ · Nature 2013What this evidence cannot show
Adult mouse, normal haematopoiesis, CXCL12 only. Cited here to support the general proposition that the niche is lineage-partitioned, which makes an environmental contribution to leukaemic lineage mechanistically plausible; it is not evidence about leukaemia or about developmental stage. Read: abstract only.
Evidence that argues against this (1)
- Lineage partition of the normal niche does not establish that leukaemic cells respect it. MLL-AF9 leukaemia stem cells were shown to home like committed myeloid progenitors rather than like HSCs and to be independent of niche-derived Wnt because their Wnt activation is cell-intrinsic, so a leukaemic cell can be indifferent to a niche signal that governs its normal counterpart. Read: abstract only. Lane SW et al. 2011
- ← related toCBFA2T3::GLIS2, inv(16)(p13.3q24.3)
Permissiveness gradient (Lopez 2019, PMID 31662298): CBFA2T3-GLIS2 in adult bone-marrow HSCs still transforms, myeloid-shifted and with much longer latency, so adult cells are less permissive rather than non-permissive.
the niche's developmental stage is the variable; adult stromal Ccl5 suppresses B-lymphoid differentiation
- related to →Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is
adds an environmental variable to an explanation that is otherwise entirely cell-intrinsic
competing account of the same age-dependent lineage phenotype, located inside the cell
predicts that the lymphoid phenotype of infant KMT2A-rearranged disease is partly environmental