Oncofusion

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Cell typestrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q4-cells

Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after

also called PreProB-progenitor · CD10-negative B-progenitor · fetal-restricted B-progenitor · CD19+CD34+CD10- progenitor

There is a B-cell progenitor that is common before birth and nearly absent in adults, and it lacks the CD10 marker that adult B-progenitors carry. Infant KMT2A leukaemia blasts are typically CD10-negative and share this cell's gene expression, which makes it a strong candidate for the cell where the disease starts.

The same thing, for a scientist

Human fetal tissues contain two distinct CD19-positive B-progenitor populations: the adult-type CD10-positive ProB-progenitor and a CD10-negative PreProB-progenitor that single-cell transcriptomics and functional assays place upstream of ProB, making it the earliest B-lymphoid-restricted progenitor of human fetal life. PreProB-progenitors make up almost one third of fetal B-progenitors but only 0.53 percent (SD 0.24) of adult bone marrow, and fetal PreProB cells carry an ontogeny-specific gene expression pattern absent from their adult counterparts that is shared with CD10-negative B-progenitor infant ALL blasts. This is the single best marker-level match between a normal fetal cell type and the immunophenotype of infant KMT2A-rearranged B-ALL.

Go deeper
The immunophenotypic coincidence that is probably not a coincidence1 deeper

Infant KMT2A-rearranged B-ALL is characteristically CD10-negative pro-B/mixed phenotype. The discovery of a normal, fetal-restricted, CD10-negative committed B-progenitor turns that clinical observation into a developmental hypothesis with a named cell.

The defining study characterised the human fetal B-cell hierarchy and reported 1:

  • Two distinct CD19-positive B-progenitors in fetal tissue: an adult-type CD10-positive ProB and a new CD10-negative PreProB.
  • Both appear early in the first trimester in embryonic liver, followed by a sustained second wave in fetal bone marrow, where together they form more than 40% of the total haematopoietic stem cell/progenitor pool.
  • Almost one third of fetal B-progenitors are CD10-negative PreProB, whereas in adult bone marrow PreProB is almost undetectable at 0.53% plus or minus 0.24%.
  • Single-cell transcriptomics plus functional assays place fetal PreProB upstream of ProB, identifying it as the first B-lymphoid-restricted progenitor in human fetal life.
  • Both fetal PreProB and fetal ProB give rise solely to B-lineage cells in vitro, yet are transcriptionally distinct from each other.
  • Fetal PreProB carries a distinct ontogeny-related gene expression pattern not seen in adult PreProB, and shares transcriptomic signatures with CD10-negative B-progenitor infant ALL blast cells.

The authors' own conclusion is the one worth quoting in the lab's grant language: this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukaemia initiation 1.

Why the 0.53% number is the load-bearing one

A cell type that constitutes roughly a third of fetal B-progenitors and 0.53% of adult bone marrow is, for practical purposes, a cell that exists only before birth 1. That is exactly the shape a cell of origin must have to explain a disease that is common in infants, rarer in older children and different in biology when it does occur later.

It also makes a prediction that is cheap to test and, as far as this cycle could establish, has not been published: if the PreProB compartment is the permissive context, then KMT2A::AFF1 cases arising in older children should either lack the PreProB signature or should have acquired it aberrantly. Either answer is informative.

Where it sits and what it does not do

Restricted, not multipotent. This is not a lympho-myeloid cell. Both fetal PreProB and ProB gave rise solely to B-lineage cells in vitro 1. That is important for the lineage-plasticity story, because it means a PreProB origin does not by itself explain lineage switch to AML. Either the leukaemia retains a more primitive LMPP-like reservoir alongside the PreProB-like bulk, or the fusion re-opens myeloid potential in a cell that had closed it. Those are distinguishable hypotheses, and the second is more interesting.

Ontology. No human-specific Cell Ontology term for the CD10-negative PreProB-progenitor was found. The nearest existing terms are CL:0002045 (fraction A pre-pro B cell, a mouse Hardy-fraction term) and CL:0000826 (pro-B cell) 2. The mismatch is itself a finding: the ontology has not caught up with human fetal B-lymphopoiesis, and anyone annotating single-cell data of infant ALL will be forced into an approximate label.

How this coexists with the fetal liver HSPC claim

The two leading origin models are not in conflict as often as they are presented. Transcriptomic matching of 124 infant B-ALL cases placed t(4;11) closest to the most immature fetal liver HSPCs and argued for a pre-VDJ origin, with only minor non-expanded B-cell clones in the BCR repertoire 3. The PreProB model points to a slightly later, already B-committed but still CD10-negative cell.

The reconciliation is that the translocation and the leukaemia need not occur in the same cell. A pre-VDJ fetal stem or multipotent cell can acquire t(4;11); the disease can then emerge in, and be maintained at, the PreProB-like stage where differentiation is blocked. Both datasets are then correct, and the BCR repertoire result is the decisive one: minor, non-expanded clones mean the founder had not yet completed V(D)J recombination 3. The Interfant cohort work independently identified the CD10-negative pro-B/mixed phenotype with NG2 expression as the hallmark immunophenotype of the disease that emerges 4.

Facts and figures
ontologyCL:0002045
ontology noteNo human-specific CL term for the CD10-negative fetal PreProB-progenitor was found; CL:0002045 (fraction A pre-pro B cell, mouse nomenclature) and CL:0000826 (pro-B cell) are the nearest approximations.
locationEmbryonic liver from early first trimester, then fetal bone marrow in a sustained second wave; almost absent from adult bone marrow
immunophenotype match to diseaseCD10-negative pro-B/mixed phenotype with NG2 expression is the hallmark immunophenotype of infant KMT2A-rearranged B-ALL
markers
[
  "CD19+",
  "CD34+",
  "CD10-",
  "CD38+/-",
  "Lineage-restricted to B"
]
frequency
[
  {
    "population": "fetal B-progenitors that are CD10-negative PreProB",
    "value": "about one third",
    "source_pmid": "31383639"
  },
  {
    "population": "PreProB-progenitors in adult bone marrow",
    "value": "0.53 percent",
    "sd": "0.24",
    "source_pmid": "31383639"
  },
  {
    "population": "B-progenitors as a share of fetal bone marrow HSC/progenitor pool",
    "value": "more than 40 percent",
    "source_pmid": "31383639"
  }
]
lineage potential
[
  "B-lineage only"
]
atlas refs
[
  {
    "label": "Human fetal B-cell developmental hierarchy with single-cell transcriptomics",
    "pmid": "31383639",
    "title": "Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs.",
    "authors": "O'Byrne S, Elliott N, Rice S, et al.",
    "venue": "Blood",
    "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": "Infant B-ALL genome-wide cohort, n=124",
    "pmid": "30679323",
    "title": "Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.",
    "authors": "Agraz-Doblas A, Bueno C, Bashford-Rogers R, et al.",
    "venue": "Haematologica",
    "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."
  }
]
How this could bite us back
  • If the disease is maintained at a B-restricted PreProB-like stage, CD19-directed therapy looks ideal on paper, which is precisely the setting in which lineage switch has been observed clinically.
  • NG2 is attractive as a KMT2A-r-specific target but was shown not to mark the leukaemia-initiating cell, so anti-NG2 therapy would reduce invasiveness without eradicating the reservoir.
  • A fetal-restricted cell type cannot be modelled in adult tissue, so preclinical systems built on adult or cord-blood cells will systematically misrepresent the disease.
Still open
  1. Do KMT2A::AFF1 cases in older children and adults carry the fetal PreProB signature, or a different, adult-type B-progenitor signature? This single comparison would strongly test the fetal-restricted-context model.
  2. If PreProB is B-restricted, what is the source of myeloid potential in lineage switch? Does the leukaemia retain a separate LMPP-like reservoir, or does the fusion re-open closed myeloid enhancers in a committed cell?
  3. Can a PreProB-like signature score be built from diagnostic RNA-seq and does it predict outcome independently of age and fusion partner?
  4. Cell Ontology lacks a human PreProB term. Should the lab propose one, so that infant ALL single-cell atlases can be annotated consistently?
Every source behind this entry (4)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Human fetal tissues contain a CD10-negative PreProB-progenitor distinct from the adult-type CD10-positive ProB-progenitor; it is the first B-lymphoid-restricted progenitor of human fetal life, constitutes almost one third of fetal B-progenitors versus 0.53 percent plus or minus 0.24 in adult bone marrow, gives rise solely to B-lineage cells, and carries a fetal ontogeny-specific gene expression pattern shared with CD10-negative B-progenitor infant ALL blasts.

    Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs · O'Byrne S, Elliott N, Rice S, Buck G, Fordham N, Garnett C, Godfrey L, Crump NT, Wright G, Inglott S, Hua P, Psaila B, Povinelli B, Knapp DJHF, Agraz-Doblas A, Bueno C, Varela I, Bennett P, Koohy H, Watt SM, Karadimitris A, Mead AJ, Ancliff P, Vyas P, Menendez P, Milne TA, Roberts I, Roy A · Blood 2019
    PMID 31383639DOI
    What this evidence cannot show

    Human fetal tissue is available only at discrete gestational windows, so the hierarchy is reconstructed rather than continuously observed. A shared transcriptomic signature between a normal fetal progenitor and leukaemic blasts is a similarity argument about cell state and does not establish that the translocation occurred in that cell. Population frequencies depend on the sorting gate and dissociation efficiency.

    Evidence that argues against this (1)
    • The PreProB compartment is defined by surface markers on sorted fetal tissue, and CD10-negativity is shared by the leukaemia — which is what makes the correspondence attractive and also what makes it weak. A leukaemia can lose CD10 without having arisen in a CD10-negative cell, and this beat elsewhere records NG2 and other markers as malleable under treatment. Oncofusion knowledge graph (internal analysis) 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    Cell Ontology contains no human-specific term for the CD10-negative fetal PreProB-progenitor; the nearest available terms are CL:0002045 (fraction A pre-pro B cell) and CL:0000826 (pro-B cell).

    Cell Ontology search for pro-B and pre-pro-B terms via the EMBL-EBI Ontology Lookup Service OLS4 API · EMBL-EBI Ontology Lookup Service; Cell Ontology consortium · Database 2026
    What this evidence cannot show

    This is a negative search result over the CL namespace at one point in time using one set of query strings; a term may exist under wording not tried, and CL is updated continuously. The Hardy fractions are mouse nomenclature and map onto human B-lymphopoiesis only approximately.

    Evidence that argues against this (1)
    • The absence of an ontology term is a statement about the ontology. It records that nobody has proposed the term, which happens for compartments that are new, species-specific or contested, and it neither supports nor undermines the compartment's existence. OBO Foundry / EMBL-EBI OLS 2026
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In 124 uniformly treated infant B-ALL cases, BCR repertoire analysis showed only minor non-expanded B-cell clones in t(4;11) disease and RNA-sequencing showed transcriptomic similarity to the most immature fetal liver HSPCs, supporting a pre-VDJ fetal origin.

    Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis · Agraz-Doblas A, Bueno C, Bashford-Rogers R, Roy A, Schneider P, Bardini M, Ballerini P, Cazzaniga G, Moreno T, Revilla C, Gut M, Valsecchi MG, Roberts I, Pieters R, De Lorenzo P, Varela I, Menendez P, Stam RW · Haematologica 2019
    PMID 30679323DOI
    What this evidence cannot show

    Bulk RNA-seq compared against bulk-sorted fetal references; 'most immature fetal liver HSPC' is a gate rather than a single cell. A pre-VDJ founder and a PreProB-like leukaemic state are compatible, so the two origin models are only partly discriminated by this dataset.

    Evidence that argues against this (1)
    • The pre-VDJ fetal-origin inference is contradicted by direct functional mapping of the leukaemia-initiating compartment in patients. In xenotransplantation of primary infant MLL-rearranged leukaemia, the cells that initiated leukaemia in MLL-AF4 patients were CD34+CD38+CD19+ and CD34-CD19+ - committed B-lineage cells - and the leukaemias they produced carried CLONAL IGH rearrangement, whereas the CD34+CD38-CD19-CD33- compartment in the same patients was enriched for NORMAL HSCs with long-term multilineage repopulating capacity and broad polyclonal IGH. Transcriptomic similarity to immature fetal-liver HSPCs and a minor BCR clone are therefore compatible with an origin in a committed, IGH-rearranged B progenitor whose program is dedifferentiated by the fusion. Aoki Y et al. 2015
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    KMT2A-rearranged infant B-ALL is associated with a pro-B/mixed phenotype and with NG2 expression, and in the Interfant cohort high NG2 expression was associated with lower event-free survival, higher numbers of circulating blasts and more frequent CNS disease or relapse.

    NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL · Prieto C, Lopez-Millan B, Roca-Ho H, Stam RW, Romero-Moya D, Rodriguez-Baena FJ, Sanjuan-Pla A, Ayllon V, Ramirez M, Bardini M, De Lorenzo P, Valsecchi MG, Stanulla M, Iglesias M, Ballerini P, Carcaboso AM, Mora J, Locatelli F, Bertaina A, Padilla L, Rodriguez-Manzaneque JC, Bueno C, Menendez P · Leukemia 2018
    PMID 28943635DOI
    What this evidence cannot show

    The same study found that NG2 is a malleable marker that does NOT enrich for leukaemia-initiating or CNS-initiating cells on serial xenotransplantation, so NG2 should be read as a state-dependent invasiveness marker rather than a stem-cell marker. Clinical associations are from a retrospective Interfant analysis.

    Evidence that argues against this (1)
    • NG2 is expressed in about 90% of KMT2A-rearranged cases, so in any cohort mixing rearranged and germline patients its associations largely re-report the rearrangement. The two NG2 items in this beat also disagree with each other: one has NG2 conferring glucocorticoid resistance through FLT3 and AP-1, the other has it as a malleable marker that does NOT enrich leukaemia-initiating cells on serial xenotransplantation. The Interfant association also travels with circulating blast count, itself among the strongest established prognostic variables, so NG2's independent contribution is not established by the correlation. Statistics in Medicine 2006
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