Oncofusion

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

Pre-B cell — the stage KMT2A::AFF1 leukaemia never reaches, and why that boundary is informative

also called precursor B cell · pre-B-I cell · large pre-B-II cell · pre-BCR-positive B progenitor

A pre-B cell is the next step after the pro-B cell: it has built a test version of its antibody receptor and uses it as a checkpoint. KMT2A::AFF1 leukaemia is blocked before this step, and which leukaemias sit before or after it is a real clinical distinction.

The same thing, for a scientist

The pre-B stage is defined by expression of a pre-B-cell receptor (rearranged immunoglobulin heavy chain paired with surrogate light chain), the checkpoint that licenses further B-cell development. Cell Ontology represents it as CL:0000817 (precursor B cell) with substages CL:0000956 (pre-B-I) and CL:0000957 (large pre-B-II). Infant KMT2A-rearranged B-ALL sits upstream of this checkpoint: the blasts are CD10-negative pro-B/mixed phenotype with a pre-VDJ, non-expanded BCR repertoire. This node exists as a deliberate negative boundary, because where a B-ALL sits relative to the pre-BCR checkpoint tracks with fusion identity, with age and with outcome, and because the checkpoint itself is a potential differentiation-therapy endpoint.

Go deeper
The boundary the disease does not cross1 deeper

Two independent data types put t(4;11) infant disease before the pre-BCR checkpoint.

Receptor genetics. BCR repertoire analysis across 124 uniformly treated infant B-ALL cases found only minor, non-expanded B-cell clones in t(4;11) disease, unlike non-KMT2A-rearranged B-ALL, which the authors interpreted as a pre-VDJ cellular origin 1. A cell that has not completed V(D)J recombination cannot have assembled a pre-BCR.

Developmental hierarchy. The normal human fetal B-progenitor hierarchy places a CD10-negative PreProB upstream of a CD10-positive ProB, and infant KMT2A-r blasts share transcriptomic signatures with CD10-negative B-progenitor infant ALL 2. Both fetal populations are B-restricted, and both lie upstream of the pre-B substages 3.

So the arrest is not merely 'immature'. It is positioned upstream of a specific, molecularly defined checkpoint, and this is a checkpoint that normally imposes both proliferation and selection.

Why a pre-BCR-upstream arrest is therapeutically awkward

Much of the success of modern B-ALL therapy leans on B-lineage identity: glucocorticoids acting on a B-progenitor transcriptional program, CD19 and CD22 as surface anchors, and asparaginase exploiting B-blast metabolism. A leukaemia arrested before the pre-BCR checkpoint is less B than a common-type CD10-positive B-ALL is. It is CD10-negative, frequently co-expresses myeloid antigens, and is glucocorticoid-resistant through an MLL-AF4-driven NG2-FLT3-NR3C1 axis 4.

That is a coherent explanation for why KMT2A-rearranged infant ALL behaves badly on a therapy backbone designed for B-ALL: the therapy assumes a degree of B-lineage commitment the cell has not reached.

Definition and substages

Cell Ontology terms retrieved directly from the ontology service 3:

CL idlabel
CL:0000817precursor B cell
CL:0000956pre-B-I cell
CL:0000957large pre-B-II cell
CL:0002052fraction D precursor B cell
CL:0000826pro-B cell (upstream)

The functional definition is the pre-B-cell receptor: a productively rearranged immunoglobulin heavy chain paired with the surrogate light chain, which signals survival and proliferative expansion and then licenses light-chain rearrangement. Immunophenotypically this is where cytoplasmic mu heavy chain appears and CD10 is retained, which is the classic 'common' or 'pre-B' B-ALL picture of older children, not the picture of infant KMT2A-r disease.

The differentiation-therapy question this node frames

If menin inhibition works by releasing a differentiation block, the honest question is: released to where? There are three possible destinations and only one of them is good.

  1. Onward through the pre-BCR checkpoint to a mature, non-proliferative B cell. This is the hoped-for outcome and the mechanism implicitly assumed by the term 'differentiation syndrome'.
  2. Sideways into a myeloid program. The MLL-Af4 human model showed that these cells can assume a myeloid state under environmental pressure while retaining lymphoid potential, and the same paper noted t(4;11) patients in whom leukaemia evaded CD19-directed therapy by undergoing myeloid lineage switch 5.
  3. Nowhere: arrest maintained by a non-menin mechanism. The undifferentiated, RAS-burdened infant subgroup is the obvious candidate, since its defining lesion is a signalling addiction rather than a chromatin one.

Which of these actually happens under a menin inhibitor, in human KMT2A::AFF1 cells, at the single-cell level, appears not to be settled. It is the question the hyp-menin-release-lineage-destination node is written to test.

Facts and figures
ontologyCL:0000817
locationFetal and postnatal bone marrow
relationship to diseaseInfant KMT2A-rearranged B-ALL is arrested UPSTREAM of this stage; the blasts are CD10-negative with a pre-VDJ, non-expanded BCR repertoire
ontology alternatives
[
  "CL:0000956",
  "CL:0000957",
  "CL:0002052"
]
markers
[
  "CD19+",
  "CD10+",
  "cytoplasmic mu heavy chain+",
  "pre-B-cell receptor (rearranged IgH plus surrogate light chain)",
  "CD34 low or negative"
]
atlas refs
[
  {
    "label": "Infant B-ALL BCR repertoire and transcriptome, 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."
  },
  {
    "label": "Human fetal B-cell developmental hierarchy",
    "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."
  }
]
How this could bite us back
  • Releasing a differentiation block in a cell arrested before lineage commitment is complete may produce myeloid rather than B maturation, converting a treatment response into a lineage switch.
  • Therapy designed for CD10-positive pre-B ALL assumes a B-lineage commitment that infant KMT2A-r blasts have not reached, which is a structural reason the standard backbone underperforms here.
  • Using CL mouse Hardy-fraction terms to annotate human infant ALL single-cell data will systematically misplace the arrest point and could make different studies look inconsistent when they are not.
Still open
  1. Under menin inhibition, do KMT2A::AFF1 blasts cross the pre-BCR checkpoint, divert to a myeloid program, or stay arrested? Single-cell transcriptome plus immunoglobulin locus readout on serial marrows from menin-inhibitor-treated patients would answer this.
  2. Is there any KMT2A::AFF1 case that presents as a pre-BCR-positive, CD10-positive B-ALL, and if so does it behave like common B-ALL rather than like infant disease?
  3. Could forcing pre-BCR signalling pharmacologically be a differentiation strategy that is safer than a general chromatin release, because it pushes toward B rather than merely unlocking?
Every source behind this entry (5)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    BCR repertoire analysis of 124 uniformly treated infant B-ALL cases found only minor, non-expanded B-cell clones in t(4;11) disease, supporting a pre-VDJ cellular origin, in contrast with non-KMT2A-rearranged B-ALL.

    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

    Repertoire sequencing depth determines whether truly minor clones are detected; absence of expansion is easier to establish than absence of rearrangement. Interfant-treated cohort, enriched for aggressive presentations.

    Evidence that argues against this (1)
    • 'Pre-VDJ' is stronger than the immunogenetic data support. Across 133 infant ALL cases, IGH was rearranged in 91%, IGK in 21%, IGL in 13% and cross-lineage TCRD in 46%; MLL-AF4 cases showed immature and oligoclonal rearrangements rather than germline configuration. The blasts have used the recombinase; they have not completed a productive VDJ and expanded a clone. Read: abstract only. Jansen MWJC et al. 2007
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The human fetal B-progenitor hierarchy places a CD10-negative PreProB-progenitor upstream of the CD10-positive ProB-progenitor, and fetal PreProB cells share transcriptomic signatures 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

    Signature sharing between a normal progenitor and leukaemic blasts is a state-similarity argument, not proof of origin.

    Evidence that argues against this (1)
    • Single-cell mapping against a developing bone-marrow reference places KMT2A-r infant B-ALL in an early lymphocyte precursor state carrying hybrid myeloid-lymphoid features, and concludes explicitly that cell of origin cannot be inferred from the transcriptional state. A shared signature with fetal PreProB therefore does not fix the leukaemia's position on the B-lineage axis. Read: abstract only. Khabirova E et al. 2022
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Cell Ontology provides CL:0000817 (precursor B cell), CL:0000956 (pre-B-I cell), CL:0000957 (large pre-B-II cell) and CL:0002052 (fraction D precursor B cell) for the pre-B stages, downstream of CL:0000826 (pro-B cell).

    Cell Ontology term lookup for pre-B and precursor B cell 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

    CL B-cell substages follow mouse Hardy fraction nomenclature and map only approximately onto human B-lymphopoiesis, which is a real annotation problem for human single-cell atlases of infant ALL.

    Evidence that argues against this (1)
    • Four ontology terms for the pre-B stages is a naming convenience. The fraction-based terms derive from murine Hardy fractions and map imperfectly onto human B-lymphopoiesis, so a resolvable identifier here can import a mouse staging scheme into a human entry. OBO Foundry / EMBL-EBI OLS 2026
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    NG2, a direct MLL-AF4 target gene, confers glucocorticoid resistance in KMT2A-rearranged B-ALL by downregulating the glucocorticoid receptor NR3C1 through FLT3 and AP-1.

    NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression · Lopez-Millan B, Rubio-Gayarre A, Vinyoles M, Trincado JL, Fraga MF, Fernandez-Fuentes N, Guerrero-Murillo M, Martinez A, Velasco-Hernandez T, Falgas A, Panisello C, Valcarcel G, Sardina JL, Lopez-Marti P, Javierre BM, Del Valle-Perez B, Garcia de Herreros A, Locatelli F, Pieters R, Bardini M, Cazzaniga G, Rodriguez-Manzaneque JC, Hanewald T, Marschalek R, Milne TA, Stam RW, Tejedor JR, Menendez P, Bueno C · Blood 2024
    PMID 39093982DOI
    What this evidence cannot show

    Mechanism largely from cell lines and xenografts; the quantitative contribution to clinical prednisone response in infants has not been prospectively measured.

    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. It is also the wrong stage: this is a pre-B entry and the NG2 biology is reported in pro-B/mixed-phenotype disease. Leukemia 2021
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MLL-Af4-transformed human cells can assume a myeloid state under environmental pressure while retaining lymphoid-lineage potential, and the same incongruity was observed in t(4;11) patients whose leukaemia evaded CD19-directed therapy by undergoing myeloid lineage switch.

    Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia · Lin S, Luo RT, Ptasinska A, Kerry J, Assi SA, Wunderlich M, Imamura T, Kaberlein JJ, Rayes A, Althoff MJ, Anastasi J, O'Brien MM, Meetei AR, Milne TA, Bonifer C, Mulloy JC, Thirman MJ · Cancer Cell 2016
    PMID 27846391DOI
    What this evidence cannot show

    The patient observation in this paper is an accompanying clinical correlate rather than a systematic case series, so it establishes existence rather than frequency.

    Evidence that argues against this (1)
    • The myeloid state can reverse. An infant with KMT2A-rearranged ALL that switched to AML on blinatumomab spontaneously reverted to the lymphoid phenotype within weeks. Retained lymphoid potential in a myeloid state is therefore not merely latent; in at least one patient the cell went back, which constrains how deep the 'block' before the pre-B checkpoint can be. Read: abstract only. Wölfl M et al. 2018
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