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Genestrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q45-immunophenotype

MME / CD10 (CALLA) - the marker this disease is defined by NOT having, and the promoter is methylated shut rather than simply not yet switched on

also called MME · CD10 · CALLA · common acute lymphocytic leukemia antigen · neprilysin · NEP · EPN · enkephalinase · P08473

CD10 is the marker that normal B cells switch on as they mature, and the classic textbook childhood leukaemia is 'common ALL' because it is CD10-positive. Infant leukaemia with a broken KMT2A gene is characteristically CD10-negative, and the interesting part is why: the CD10 gene's switch is not merely un-flipped, it is chemically locked shut by DNA methylation.

The same thing, for a scientist

MME (UniProt **P08473**, **NEP_HUMAN**, **750 aa**, single reviewed human record, primary gene name MME, synonym EPN) encodes **neprilysin**, the zinc metalloendopeptidase known in haematology as **CD10** or the **common acute lymphocytic leukaemia antigen (CALLA)**. Note the trap: the UniProt entry name is NEP_HUMAN and the protein name is Neprilysin - **neither the gene symbol nor the UniProt id contains the string CD10 or MME's clinical name**, which is why this marker is easy to lose in a symbol-keyed search. **CD10-negativity is the diagnostic fingerprint of this disease.** KMT2A-rearranged infant ALL presents as pro-B / EGIL BI: CD19-positive, CD22 and CD79a-positive, **CD10-negative**, with aberrant CD15/CD65 co-expression [E1][E2]. Behm's founding NG2 series found NG2-positive cases significantly more likely to be CD10-negative [E3]; Schwartz found NG2 positivity associated with a CD10-negative phenotype in adults [E4]; in 377 B-ALL, **CD10 is one of the five markers in the ROC-derived t(11q23) flow score (NG2, CD10, CD15, CD34, CD20; sensitivity 84.21%, specificity 99.04%)**, and it is in the score *negatively* [E5]. **The stage interpretation is incomplete, and one paper shows why.** Ikawa 2010 looked at the discordance that had been noticed for years: CD10-negativity supposedly reflects an earlier B-cell stage, yet **complete VDJH immunoglobulin heavy-chain rearrangements with productive joints are found in almost half of infant ALL patients** - a more mature genotype than the immunophenotype implies. Bisulfite sequencing of the CD10 type 1 and type 2 promoters found **more than 84% of identified CpG dinucleotides methylated in all three CD10-negative infant MLL/AF4 samples**, with the CpGs in the Sp1-binding clusters and functionally active regulatory regions **fully methylated**, while **none** of the CpGs were methylated in CD10-positive ALL samples [E6]. **So CD10-negativity here is active epigenetic silencing of a locus in a cell that has already rearranged its immunoglobulin genes, not a cell caught before the switch.** That is a different biological claim from "arrested at the pro-B stage", and it is the claim this entry makes. **And CD10-negative pre-B ALL belongs with pro-B ALL, not with pre-B ALL.** Attarbaschi 2006 found MLL rearrangement in **15 of 29 pro-B ALL and 7 of 11 CD10-negative pre-B ALL**, and in **none** of the CD10-positive pre-B or common ALL patients; the two CD10-negative subsets shared clinical features and CDw65/CD15 co-expression [E7].

Go deeper
What CD10-negativity does and does not license

Licenses: a same-day hypothesis of KMT2A rearrangement in an infant, strong enough that CD10 earns a place in a validated flow score 5; and grouping CD10-negative pre-B ALL with pro-B ALL for trial purposes 7.

Does not license: the inference that the blast is developmentally frozen before the CD10 stage. Half of these patients have completed productive VDJH joins 6, and this graph's concept-proximal-vdj-bias-and-ig-mrd-in-kmt2a-aff1 and hyp-ig-mrd-fails-where-the-repertoire-is-proximally-biased depend on exactly that repertoire being present. An entry that calls these cells 'arrested before CD10' and an entry that uses their IGH rearrangements for MRD cannot both be describing the same cell under the same model - and the methylation result reconciles them: the differentiation machinery ran, and the CD10 locus specifically was silenced.

Nor does it license a per-patient rule. This graph already carries cell-type-fetal-preprob-cd10-negative, the normal counterpart; CD10-negativity is a property of a developmental window as well as of this leukaemia, and roughly 50% of childhood pro-B ALL is not MLL-rearranged 7.

Cell type, cell state, localisation, epigenetics
  • Cell type. Normally induced at the common/pre-B stage of B lymphopoiesis; also on kidney proximal tubule brush border, intestinal brush border, neutrophils and many stromal cells - neprilysin is a widely expressed peptidase and CD10 is not a B-cell-specific antigen.
  • Cell state. In KMT2A-rearranged infant ALL, off - and off by methylation, not by absence of the upstream signal 6.
  • Localisation. Type II transmembrane ectoenzyme at the plasma membrane, 750 residues, catalytically active zinc metalloendopeptidase 8. Unusually among the markers in this beat it has a known enzymatic function in its own right: it degrades enkephalins, substance P, bradykinin, atrial natriuretic peptide and amyloid-beta.
  • Epigenetics. Dense CpG methylation of the type 1 and type 2 CD10 promoters, Sp1-site clusters fully methylated, in CD10-negative infant MLL/AF4 6. This is the only marker in this beat whose OFF state has a published chromatin mechanism, and it is the mirror image of gene-cspg4 and gene-prom1, whose ON states do.
Facts and figures
uniprotP08473
gene symbolMME
length AA750
cd numberCD10
alias hazardgene symbol MME; UniProt entry name NEP_HUMAN; protein neprilysin; clinical names CD10 and CALLA. Four non-overlapping vocabularies for one molecule.
accession resolutiongene_exact:MME AND organism_id:9606 AND reviewed:true, fields include gene_primary and length; one row; primary name read back as MME; length 750 asserted for verify-accessions.py.
other names
[
  "CALLA",
  "neprilysin",
  "NEP",
  "enkephalinase",
  "EC 3.4.24.11"
]
silencing mechanism
{
  "finding": ">84% of identified CpGs methylated in CD10 type 1 and type 2 promoters in 3/3 CD10-negative infant MLL/AF4 samples; Sp1-site clusters fully methylated; 0% methylation in CD10-positive ALL",
  "n": 3,
  "pmid": "20051780",
  "title": "Dense methylation of types 1 and 2 regulatory regions of the CD10 gene promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene.",
  "authors": "Ikawa Y, Sugimoto N, Koizumi S, et al.",
  "venue": "J Pediatr Hematol Oncol",
  "year": 2010,
  "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."
}
genotype association
{
  "mll_r_in_pro_B_ALL": "15/29",
  "mll_r_in_CD10_negative_pre_B_ALL": "7/11",
  "mll_r_in_CD10_positive_pre_B_and_common_ALL": "0/328",
  "pmid": "16707593",
  "title": "Mixed lineage leukemia-rearranged childhood pro-B and CD10-negative pre-B acute lymphoblastic leukemia constitute a distinct clinical entity.",
  "authors": "Attarbaschi A, Mann G, König M, et al.",
  "venue": "Clin Cancer Res",
  "year": 2006,
  "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."
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.0374,
  "chronos_mean_other_leukaemia": -0.0316,
  "difference": -0.0058,
  "pan_essentiality_all_lines": -0.0069,
  "selectivity_rank": 8390,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}
How this could bite us back
  • CD10-negativity is a triage signal that fails in both directions. Roughly half of childhood pro-B ALL is MLL-germline, and NG2-positive cases occur among CD10-positive common ALL, so a protocol that uses CD10 status to decide whether to run KMT2A FISH will both over-test and miss cases.
  • If CD10 is silenced by promoter methylation rather than by developmental stage, then a hypomethylating agent given for any reason could re-express CD10 and change the blast's flow phenotype without changing the disease. Azacitidine and decitabine are in combination regimens with menin inhibitors in this disease, and no study found here reports CD10 before and after.
  • MME is neprilysin, an active enzyme with broad tissue distribution and a marketed inhibitor (sacubitril). Any proposal to manipulate CD10 pharmacologically in leukaemia inherits cardiovascular and renal peptide biology that has nothing to do with the blast.
  • The entry that says these cells are arrested before the CD10 stage and the entries that use their completed IGH rearrangements for MRD describe the same cell under incompatible models. The methylation result reconciles them, and any MRD argument that leans on 'immature pro-B' as a reason for a proximal VDJ repertoire needs to state which model it is using.
Still open
  1. Does a hypomethylating agent restore CD10 expression in KMT2A::AFF1 infant blasts? A single in vitro experiment would convert a three-patient correlation into a mechanism, and azacitidine combinations are already being given in this disease.
  2. Does the MLL-AF4 fusion cause the CD10 promoter methylation, or is the methylation a downstream consequence of the locus being off? No targeted-editing or fusion-knockdown experiment on the MME promoter was found in this beat.
  3. Is the CD10 promoter methylated in KMT2A-germline CD10-negative pro-B ALL - the roughly half of pro-B cases without the rearrangement? If yes, the methylation is a property of the differentiation state and not of the fusion.
  4. Does CD10 appear or change at lineage switch, and in what order relative to CD19 loss and myeloid antigen gain?
Every source behind this entry (8)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    The EGIL immunological classification defines the most immature B-lineage class (BI, pro-B ALL) by expression of CD19 and/or CD79a and/or CD22 with no expression of later B-differentiation markers, and provides a scoring system to distinguish biphenotypic acute leukaemia from acute leukaemias merely expressing a marker of another lineage.

    PMID 7564526
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **A consensus proposal from 1995, not a measurement**, and the authors describe it as requiring reproducibility testing. Superseded for lineage assignment in mixed-phenotype leukaemia by WHO and ICC criteria, which use different and generally stricter thresholds. Cited here only to define what pro-B/BI means, because the whole CD10-negative argument is expressed in that vocabulary. PubMed returns no DOI for this record.

    Evidence that argues against this (1)
    • EGIL and WHO 2008 criteria classify overlapping but different sets of patients as mixed-phenotype, and current WHO/ICC classification recognises MPAL with KMT2A rearrangement as its own genetic entity. A CD10-negative pro-B description in EGIL vocabulary is not a stable identity across classification eras. Leventaki V et al. 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

    KMT2A-rearranged paediatric ALL typically shows an immature pro-B immunophenotype with expression of CD19 and CD34 and co-expression of CD15, CD33, CD65 and CD68, often lacking CD10, and expresses NG2/CSPG4 in about 90% of cases.

    PMID 36979800DOI
    What this evidence cannot show

    **Narrative review, cited as a map.** Abstract read in full from raw efetch XML on 2026-09-20; full text not read. 'Often lacking CD10' is deliberately softer than the textbook 'CD10-negative', and the softer version is the accurate one - the primary data show CD10-negative pre-B and pro-B both occur and both carry MLL rearrangements at similar rates [E7].

    Evidence that argues against this (1)
    • The same review states NG2 expression in about 90% of cases, which is higher than every primary measurement found in this beat (81% sensitivity at n=533; 0.89 in adult B-precursor ALL). Review-level marker percentages in this area run optimistic and should not be used as numbers. Wuchter C et al. 2000
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Among 104 consecutive children with ALL screened prospectively with monoclonal antibody 7.1, NG2-positive cases were significantly more likely to be infants, to have hyperleukocytosis and central nervous system involvement, to be CD10-negative, and to express the myeloid-associated antigens CD15 and CD65; all 9 NG2-positive cases carried t(4;11) or t(11;19) with MLL rearrangement.

    PMID 8562939
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **The CD10-negative association rests on 9 positive cases.** It is corroborated independently in adults [E4] and in a flow scoring system [E5], which is why it is carried at established confidence, but this paper alone would not support it. PubMed returns no DOI for this record.

    Evidence that argues against this (1)
    • CD10-negativity is also a property of normal fetal pre-pro-B cells, which this graph carries as cell-type-fetal-preprob-cd10-negative. An association between CD10-negativity and a rearrangement in a disease of fetal origin may be partly an association between the disease's cell of origin and its normal counterpart, rather than an effect of the rearrangement. Ikawa Y et al. 2010
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In adult B-precursor ALL, NG2 expression was significantly associated with a CD10-negative, CD34-negative, CD24-negative, CD65s-positive, CD15-positive, CD13-negative, CD33-negative phenotype, and NG2 predicted MLL rearrangement with 100% accuracy among patients with a CD65s-positive and/or CD15-positive immunophenotype.

    PMID 12886247DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **Adult ALL**, so this corroborates the CD10-negative association across age but does not measure it in infants. NG2 was nonetheless positive in 2% of common ALL - which is by definition CD10-positive - so the association is not absolute.

    Evidence that argues against this (1)
    • NG2 was positive in 2% of common ALL in this same series, and common ALL is CD10-positive by definition. CD10-positivity therefore does not exclude a KMT2A rearrangement, and any triage rule that uses CD10-positivity to stop looking will miss cases. Schwartz S et al. 2003
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In a retrospective flow cytometric analysis of 377 patients with B-ALL against interphase FISH, ROC analysis selected NG2, CD10, CD15, CD34 and CD20 for a predictive score for t(11q23), which achieved sensitivity 84.21% and specificity 99.04%; separate scores used CD27, CD9, CD66c, CD10, CD25 and CD34 for t(12;21), CD25, CD38, CD34 and CD66c for t(9;22), and CD34, cytoplasmic mu, CD123 and CD66c for t(1;19).

    PMID 30730614DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **Retrospective, single-centre, n = 377, scores derived and evaluated in the same cohort** - the authors explicitly call for prospective evaluation, so 84.21%/99.04% are optimistic by construction. The abstract does not state the direction of each marker's contribution; CD10 is carried here as contributing negatively on the basis of the independent CD10-negativity literature [E3][E4][E7], not on this paper's own text.

    Evidence that argues against this (1)
    • That NG2 alone reaches sensitivity 0.89 in adult B-precursor ALL while the five-marker score reaches 84.21% suggests the additional markers, CD10 among them, may be adding little beyond NG2. A multi-marker score that does not beat its best single marker is a warning about derivation-set optimism, not a validation. Schwartz S et al. 2003
  6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    The CD10-negative immunophenotype of infant ALL is a hallmark and a predictable signature of MLL rearrangement, but although CD10-negativity reflects an earlier stage of B-cell development, complete VDJH rearrangements are found in almost half of patients, indicating a more mature IgH status than the immunophenotype implies. Three of four infant ALL samples studied showed complete productive VDJH rearrangements. Bisulfite sequencing of the CD10 type 1 and type 2 promoters found more than 84% of identified CpG dinucleotides methylated in all three CD10-negative infant ALL samples with MLL/AF4, with CpGs in the clusters of putative Sp1-binding sites and in functionally active regulatory regions fully methylated, whereas none of the CpGs were methylated in CD10-positive ALL samples. The authors conclude that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism.

    PMID 20051780DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **n = 3 CD10-negative infant MLL/AF4 samples against a small set of comparators including one cell line.** The methylation-versus-expression contrast is complete and clean in those three, which is why it is compelling, but three patients cannot establish a general mechanism. **Correlation, not causation**: nothing here demonstrates that demethylating the promoter restores CD10, nor that the MLL-AF4 fusion causes the methylation. The 'almost half of patients' VDJH figure is cited by the authors from prior literature, not measured here.

    Evidence that argues against this (1)
    • Dense promoter methylation of a silent gene is the expected state of many silent genes and can be a consequence of the locus being off rather than the cause. Distinguishing the two requires a demethylation or targeted-editing experiment that this paper does not perform, and none was found in this beat. Ikawa Y et al. 2010
  7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Among Austrian multicentre ALL trial patients analysed by conventional cytogenetics and MLL split-apart FISH, MLL rearrangement was found in 15 of 29 pro-B ALL, 7 of 11 CD10-negative pre-B ALL and 1 of 2 FAB L1 mature B-cell leukaemia cases, but in none of the CD10-positive pre-B patients (23 with CD10 on 20-80% of blasts plus 136 with CD10 on 80% or more) or common ALL patients (26 with CD10 on 20-80% plus 143 with CD10 on 80% or more). MLL-rearranged pro-B and CD10-negative pre-B ALL cases had similar clinical and immunophenotypic features at diagnosis, including co-expression of CDw65 and CD15.

    PMID 16707593DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **Roughly half of pro-B ALL cases were MLL-germline (15 of 29), so CD10-negativity is far from sufficient for the genotype.** The zero MLL rearrangements among 328 CD10-positive patients is the strong half of the result and rests on cytogenetics plus split-apart FISH, which can miss cryptic rearrangements. The authors' own conclusion that CD10-negative pre-B cases are really pro-B cases that retained the ability to rearrange IGH is explicitly flagged by them as requiring direct experimental data.

    Evidence that argues against this (1)
    • Fifteen of 29 pro-B ALL cases in this series had NO MLL rearrangement. A CD10-negative pro-B immunophenotype therefore carries roughly even odds for the genotype in this cohort, which is far weaker than NG2 and is the reason CD10-negativity cannot stand alone as a genotype surrogate. Attarbaschi A et al. 2006
  8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    MME is UniProt P08473, entry name NEP_HUMAN, protein name Neprilysin (EC 3.4.24.11), also known as atriopeptidase and as the common acute lymphocytic leukaemia antigen, 750 amino acids, a single reviewed human record with primary gene name MME and gene synonym EPN.

    What this evidence cannot show

    Fetched 2026-09-20 with `gene_exact:MME AND organism_id:9606 AND reviewed:true`, requesting `gene_primary` and `length` per rules 62 and 65; primary name read back as MME; exactly one reviewed row; length 750 asserted so `verify-accessions.py` can catch a swap. **This is the worst alias case in the beat: the gene symbol is MME, the UniProt entry name is NEP_HUMAN, the protein is neprilysin, and the clinical names are CD10 and CALLA.** Four vocabularies, no overlap, and a search keyed to any one of them misses the other three.

    Evidence that argues against this (1)
    • Neprilysin is a widely expressed active peptidase - kidney brush border, intestine, neutrophils, stroma - and is the target of the heart-failure drug sacubitril. Reading CD10 as a B-lineage differentiation marker is a haematology convention, not a property of the protein, and any CD10-directed agent would not be haematopoiesis-restricted. UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
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