The cell CALM-AF10 arrests: an early T-precursor in adults and a TCR-positive thymocyte in children - two states, split by age (corrected 2026-09-21)
also called CALM-AF10 T-ALL cell of origin · gamma-delta precursor arrest
When CALM-AF10 causes T-cell leukaemia, it is almost always in a particular early kind of T cell - the gamma-delta lineage or an even earlier precursor - and essentially never in the commoner alpha-beta lineage. Which of those two it is predicts whether the patient survives.
The same thing, for a scientist
Within T-ALL, CALM-AF10 is **lineage-restricted**: absent from TCR-alpha-beta-lineage cases, present in **19% of TCR-gamma-delta** and **33% of immature delta/gamma** T-ALLs [E1]. The immature cases differ from their CALM-AF10-negative counterparts by a **CD5+/CD2-** phenotype and by their TCR-gamma and TCR-delta configurations, which is the argument that they are **TCR-gamma-delta precursors** rather than a separate immature compartment [E1]. About **half of PICALM::MLLT10 T-ALL is ETP-ALL** [E2]. Immunophenotype in one institutional series was **pro-/pre-T, CD4/CD8 double-negative, CD7-positive, with frequent CD79a expression** [E2]. **The arrest stage, not the fusion, carries the prognosis**: 3 of 3 adults and 5 of 5 children with CALM-AF10-positive TCR-gamma-delta T-ALL were alive in remission, against 8 of 9 adults dead and 2 of 3 children relapsed among the immature cases [E1]. The same split reappears as an adult-only ETP effect in the largest aggregate [E2].
The 5' versus 3' transcript observation, which nobody has followed up
Nine of twelve immature CALM-AF10 T-ALLs showed 3' fusion transcripts, whereas six of seven TCR-gamma-delta cases showed 5' fusion transcripts - and the 5' transcripts retain the AF10 extended LAP/PHD (PZP) region required for homo-oligomerisation 1. If that association holds, breakpoint position tracks arrest stage tracks outcome, and the mechanistic link would be the very PZP module that abolishes transformation when restored in cis. This is a 2003 observation on small numbers that appears to have been left alone; it is one of the more testable loose ends in this beat.
What the state means for a targeted agent
Two consequences. First, the surface. CD7 is essentially universal here, including on the CALM-AF10-positive non-T acute leukaemias, which all expressed CD7 and carried T-restricted TCR-delta rearrangements 1; frequent CD79a in a T-lineage disease is the kind of cross-lineage marker that confounds flow-based MRD. Second, the comparator. Any trial arm in this fusion will be dominated by immature and ETP cases, which have their own poor prognosis; a targeted agent tested there is tested against a maturation-stage confounder that is larger than most drug effects.
CORRECTION, 2026-09-21: this is two cell states, split by age, and one lineage switch
A prospective molecular screen separates the two states this entry's title runs together. Adult CALM-AF10-positive T-ALL is predominantly (72%) surface CD3/T-cell-receptor NEGATIVE, and 82% of those are early T-cell precursor. Paediatric CALM-AF10-positive T-ALL is predominantly (67%) T-cell-receptor POSITIVE. In the same cohort the poor event-free and overall survival were restricted to the TCR-negative adults, while ETP-ALL as such carried no prognostic impact - so the arrest stage, not the fusion and not the ETP label, is what tracked outcome.
A pooled series reporting 'about half ETP' across children and adults is therefore averaging two populations. And the state is not fixed within a patient: an adolescent PICALM::MLLT10 T-ALL with a cortical thymocyte, non-ETP phenotype relapsed six years later as acute myeloid leukaemia, with cooperating lesions accumulated in between. This entry should be read as describing a distribution of arrest stages that shifts with age and can be left, not a single cell state the fusion imposes.
| ontology | CL:0000827 (pro-T cell) is the closest available term; no ontology term distinguishes a TCR-gamma-delta precursor from an early T-precursor |
|---|---|
| lineage restriction | absent from TCR-alpha-beta lineage T-ALL; present in TCR-gamma-delta (19%) and immature delta/gamma (33%) |
| etp fraction of picalm mllt10 t all | 0.5 |
| location | thymus / early T-lineage compartment |
| outcome split | TCR-gamma-delta arrest: favourable in the founding series (8/8 alive). Immature arrest: poor (3/12 alive). Adult ETP-ALL inferior to adult non-ETP; no paediatric ETP effect. |
| untested association | 5' fusion transcripts (PZP-retaining) associate with the gamma-delta phenotype and 3' transcripts with the immature phenotype; breakpoint position may therefore track arrest stage and outcome |
markers
[ "CD7 positive", "CD4/CD8 double negative", "CD5 positive / CD2 negative in the immature CALM-AF10 subset", "CD79a frequently positive", "cytoplasmic TCR-beta negative in immature cases" ]
- The mouse models produce AML and the patients mostly have T-ALL. Every mechanistic result in this beat therefore comes from the minority lineage of the human disease.
- Any trial arm here will be dominated by immature and ETP cases whose maturation-stage prognosis is larger than most drug effects; a single-arm response rate will be uninterpretable without stage stratification.
- Does fusion-transcript type (5' versus 3') really track arrest stage and outcome? It is a 2003 observation on 19 patients that nobody appears to have retested with modern RNA sequencing, and it would connect breakpoint position to the PZP brake.
- Why is PICALM::MLLT10 T-lineage-skewed while KMT2A::MLLT10 is myeloid-skewed, given the identical AF10 module? Nothing in this beat's reading isolates the determinant.
- Is there a normal TCR-gamma-delta precursor in which CALM-AF10 is uniquely transforming? All the mouse models start from bone-marrow HSPCs or fetal liver and produce myeloid disease, which is the minority lineage in patients.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CALM-AF10 was found in 12 of 131 unselected T-ALLs, absent from TCR-alpha-beta lineage cases, present in 19% of TCR-gamma-delta and 33% of immature delta/gamma T-ALLs; immature CALM-AF10 cases were CD5+/CD2- and carried TCR-gamma/delta configurations suggesting they are TCR-gamma-delta precursors; 9 of 12 immature cases showed 3' fusion transcripts while 6 of 7 TCR-gamma-delta cases showed 5' transcripts retaining the AF10 extended LAP/PHD domain; all 8 patients with CALM-AF10-positive TCR-gamma-delta T-ALL were alive, against 3 of 12 with immature CALM-AF10 T-ALL.
CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage. · Asnafi V, et al. · Blood 2003What this evidence cannot show
Single large European cohort, adults and children pooled, and the outcome contrast rests on 8 versus 12 patients. Only about half the positive cases showed t(10;11) by classical cytogenetics, so karyotype-only series will undercount the fusion and enrich for whichever subgroup is cytogenetically visible.
Evidence that argues against this (1)
- A later paediatric T-ALL series found no statistically significant outcome difference between PICALM::MLLT10-positive and -negative children (5-year EFS 71.4% versus 62.5%), so the fusion's prognostic weight in unselected paediatric T-ALL is contested even where the maturation split is not. Lo Nigro L et al. 2013
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Across 156 PICALM::MLLT10 acute leukaemias, T-ALL constituted 65% of cases and about half of those were ETP-ALL; the institutional cohort's T-ALL cases were pro-/pre-T, CD4/CD8 double-negative, CD7-positive with frequent CD79a expression; adult but not paediatric ETP-ALL patients had inferior survival compared with non-ETP-ALL.
Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion. · Wang J, et al. · Hum Pathol 2024What this evidence cannot show
144 of 156 patients pooled from the literature, so immunophenotype detail comes from the 12 institutional cases only. ETP classification criteria have changed over the period the pooled cases span.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT, and it splits this entry's cell state by AGE. A prospective molecular screen found CALM-AF10 in 30 of 431 (7%) T-ALL patients aged 16 and over and 15 of 234 (6%) aged up to 15, and the two groups arrest differently: ADULT CALM-AF10 patients were predominantly (72%) negative for surface CD3/T-cell receptor, whereas CHILDREN were predominantly (67%) POSITIVE for T-cell receptor. Among the TCR-negative adults, 82% had an early T-cell precursor phenotype. So a pooled 156-case series reporting 'about half ETP' is averaging a mostly-ETP adult population with a mostly-TCR-positive paediatric one, and the arrest is not one state. Ben Abdelali R et al. 2013
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CALM-AF10-positive T-ALL overexpresses HOXA genes and BMI1 relative to other T-ALL.
CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. · Dik WA, et al. · Leukemia 2005What this evidence cannot show
Expression profiling; small CALM-AF10 numbers. Establishes the transcriptional state, not the cell of origin.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT: the state is not stable within a patient. An adolescent PICALM::MLLT10-positive T-ALL with a CORTICAL THYMOCYTE, NON-ETP phenotype achieved complete remission and relapsed six years later as acute myeloid leukaemia, with del(5q), del(17p) and 17q gain, and NF1, EZH2, SMC1A and PHF6 mutations accumulating. A therapy-resistant fusion-positive progenitor persisted through remission and re-emerged across a lineage boundary. An expression signature measured at diagnosis therefore describes a state the clone can leave, and 'the cell CALM-AF10 arrests' should not be written as though the arrest were terminal. Kawamura M et al. 2026
TCR-gamma-delta precursor or early T-precursor
about half of PICALM::MLLT10 T-ALL is ETP-ALL
arrest at a gamma-delta precursor or ETP stage
19% of TCR-gamma-delta and 33% of immature delta/gamma T-ALL
- ← related toWhere the break falls, and the three incompatible numbering frames that make it easy to get wrong
5' versus 3' transcript type associates with maturation stage and outcome
- related to →The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia
corrected 2026-09-21: the arrest stage splits by age (72% of adults TCR-negative, 67% of children TCR-positive) and a documented lineage switch to AML shows it can be left
the state belongs to the FUSION, not to PICALM - any heterologous NES substitutes for the CALM contribution
two mechanistically unrelated KMT2A-free HOXA-high fusions restricted to the same arrested cell state