SET::NUP214 adult T-ALL is gamma-delta-lineage-restricted and resistant to steroids and chemotherapy early - the same cell state CALM-AF10 occupies
also called SET-NUP214 gamma-delta T-ALL · TCR-negative T-ALL with SET-NUP214 · immature T-ALL cell state
Patients whose T-cell leukaemia carries SET::NUP214 almost all have the same immature, gamma-delta type of T cell, and their disease barely responds to steroids or the first round of chemotherapy - though with transplant their final outcomes end up similar to everyone else's.
The same thing, for a scientist
In the French **GRAALL 2003/2005** adult T-ALL trials, 11 of 196 patients (**6%**) carried a SET-NUP214 transcript. **Ten of the eleven (91%) were TCR-negative and the fusion was strikingly associated with the TCR gamma-delta lineage**, defined by TCRgamma-delta expression, TCRdelta and/or TCRgamma rearrangement with no complete TCRbeta VDJ rearrangement in surface-CD3/TCR-negative cases [E1]. **The early treatment response is markedly worse and the final outcome is not:** corticosteroid resistance **91% versus 44% (P = .003)**, chemotherapy resistance **100% versus 44% (P = .0001)**, yet all but one achieved complete remission, nine were allografted, and overall outcome did not differ from SET-NUP214-negative patients [E1]. **The transplant result is worse than that reads.** A separate single-centre series of 11 SET-NUP214 acute-leukaemia patients (5 AML, 6 T-ALL) all transplanted in CR1 with myeloablative conditioning reports **relapse in 60% of the AML and 50% of the T-ALL cases post-transplant**, with estimated 3-year overall and leukaemia-free survival of **38.5%** [E2]. So the GRAALL outcome equivalence should be read as 'equivalent within a cohort in which most were transplanted', not as a benign prognosis. **The differentiation phenotype is reproduced in vitro.** SET-NUP214 knockdown in LOUCY induces differentiation, with the founding study's own flow readout being **TCRgamma-delta and membrane CD3 surface expression** [E3]. **Why this is in the graph.** This graph already carries `cell-state-tcr-gamma-delta-precursor-arrest-calm-af10`. **Two mechanistically unrelated, KMT2A-free, HOXA-high fusions are restricted to the same arrested cell state** - which is either a shared cell of origin or a shared programme, and either answer is load-bearing for whether HOXA-high is a lesion property or a cell-state property. **This is ADULT T-ALL. Two steps from infant B-lineage KMT2A::AFF1: lineage and age both differ.**
What 'gamma-delta lineage' means here, and why it is not a surface phenotype
The GRAALL definition is rearrangement-based, not marker-based: TCRgamma-delta expression, or TCRdelta and/or TCRgamma rearrangement with no complete TCRbeta VDJ rearrangement in cases that are surface CD3/TCR-negative 1. Ten of eleven cases were TCR-negative, so most of these patients were assigned to the gamma-delta lineage by their rearrangement status while expressing no surface TCR at all.
That matters for two reasons. First, it is a claim about where the cell stopped, not about what it is - an immature thymocyte that rearranged TCRdelta/gamma before arresting. Second, a reader comparing this to a flow-defined gamma-delta population elsewhere in the graph is comparing two different measurements with the same name.
The reverse observation supports the arrest reading: knocking the fusion down in LOUCY turns TCRgamma-delta and membrane CD3 on 3. The fusion is holding the cell before that step.
The co-mutation landscape, which is small and consistent
In a 96-patient Chinese T-ALL series, SET-NUP214 rearrangement was one of the three genetic markers most frequently associated with PHF6 mutation (P = .002), alongside NOTCH1 (P = .003) and JAK1 (P = .005); SET-NUP214 itself was present in 3 of 48 (6.3%) and CALM-AF10 in 0 of 48 4.
PHF6 is a PHD-finger chromatin protein and an X-linked tumour suppressor in T-ALL. The association is statistical, in a series where the fusion appears three times, so it is a lead and not a mechanism - but it is the only recurrent co-lesion this beat found, and it points at chromatin rather than at signalling.
| ontology | CL:0000798 (gamma-delta T cell lineage, as an approximation - the patients are arrested precursors, mostly surface TCR-negative) |
|---|---|
| location | thymus / T-lineage precursor compartment |
| lineage definition is | rearrangement-based, not surface-marker-based - do not compare directly with a flow-defined gamma-delta population |
| shared state with | cell-state-tcr-gamma-delta-precursor-arrest-calm-af10 |
| age | adult (GRAALL); the founding mechanistic paper is paediatric |
markers
[ "TCR-negative in 10 of 11 GRAALL cases", "TCRdelta and/or TCRgamma rearranged without complete TCRbeta VDJ", "TCRgamma-delta and membrane CD3 appear when the fusion is knocked down" ]
treatment response
{
"corticosteroid_resistance_pct": 91,
"corticosteroid_resistance_comparator_pct": 44,
"corticosteroid_p": 0.003,
"chemotherapy_resistance_pct": 100,
"chemotherapy_resistance_comparator_pct": 44,
"chemotherapy_p": 0.0001,
"n_positive": 11,
"n_cohort": 196,
"cohort": "GRAALL 2003 and 2005, adult"
}post transplant
{
"n": 11,
"aml_relapse_pct": 60,
"tall_relapse_pct": 50,
"os_1y_pct": 69.3,
"os_3y_pct": 38.5,
"lfs_3y_pct": 38.5,
"source": "single centre, retrospective, AML and T-ALL pooled"
}co lesions
[ "PHF6 mutation (P = .002)", "NOTCH1 mutation", "JAK1 mutation" ]
- 100% early chemotherapy resistance means any new agent evaluated in this genotype is being added to a failing backbone, which flatters single-agent response rates and makes combination attribution hard.
- The differentiation induced by fusion knockdown is toward TCRgamma-delta and CD3 expression; a differentiation-inducing drug in this genotype would carry differentiation-syndrome risk, and no published experience exists.
- Transplant is already standard in most of these patients and half of them still relapse, so the unmet need is post-transplant disease control, where menin inhibitors and CRM1 inhibitors have completely different toxicity profiles and neither has been tried.
- Is the gamma-delta restriction caused by the fusion or by the cell the fusion lands in? CALM-AF10 shows the same restriction by an unrelated mechanism, which argues for the cell rather than the lesion - and if so, HOXA-high in T-ALL is partly a cell-state readout.
- Why is early treatment resistance so severe while final outcome is not? The obvious answer is transplant, and the transplant series says relapse is common, so the two datasets may simply be describing a disease that is hard to clear at every stage.
- Does the NF-kB tethering documented for this fusion contribute to the corticosteroid resistance? Glucocorticoid receptor and NF-kB are mutually antagonistic, and nobody has connected the two observations.
- Is there an MRD assay for this fusion in routine use? Three children with SET-NUP214 have had MRD tracked in one report, but nothing in this beat establishes a standard.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In ADULT human T-ALL on GRAALL 2003 and 2005, 11 of 196 patients (6%) carried a SET-NUP214 transcript; 10 of 11 (91%) were TCR-negative and the fusion was strikingly associated with TCR gamma-delta lineage T-ALL as defined by TCRgamma-delta expression, TCRdelta and/or TCRgamma rearrangement but no complete TCRbeta VDJ rearrangement in surface CD3/TCR-negative cases; corticosteroid resistance was 91% versus 44% (P = .003) and chemotherapy resistance 100% versus 44% (P = .0001), yet all but one achieved complete remission, nine were allografted, and outcome did not differ from SET-NUP214-negative patients.
SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL. · Ben Abdelali R, et al. · Blood 2014What this evidence cannot show
ADULT T-ALL, n = 11 positive patients. The resistance percentages rest on eleven people; 91% is 10/11 and 100% is 11/11, so a single reclassification moves the first figure by nine points. The outcome equivalence is badly underpowered to exclude a real difference and is confounded by transplant in nine of eleven. The gamma-delta assignment is rearrangement-based in mostly TCR-negative cases, so it is a lineage inference rather than a surface phenotype.
Evidence that argues against this (1)
- A separate transplanted series reports a high relapse rate after allogeneic transplant in CR1 for SET-NUP214 acute leukaemia - 60% of AML and 50% of T-ALL cases - with estimated 3-year overall and leukaemia-free survival of 38.5%, so 'outcome did not differ' in GRAALL should not be read as a good prognosis. Shen Y et al. 2023
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a single-centre retrospective series of 11 acute-leukaemia patients with SET-NUP214 fusion (5 AML, 6 de novo T-ALL) all transplanted in CR1 with myeloablative conditioning between July 2017 and November 2022, 3 of 5 AML (60%) and 3 of 6 T-ALL (50%) relapsed post-transplant; estimated 1-year and 3-year overall survival were 69.3% and 38.5%, with identical leukaemia-free survival figures.
The outcome of acute leukemia patients with SET-NUP214 fusion after allogeneic stem cell transplantation. · Shen Y, et al. · Front Oncol 2023What this evidence cannot show
Single centre, retrospective, n = 11, mixed AML and T-ALL pooled into one survival estimate, no comparator arm, and a maximum follow-up of about five years for a 3-year estimate. Identical OS and LFS figures at both timepoints suggest every death followed relapse, which is plausible but unstated. Abstract-level for this beat. The authors themselves say larger studies are urgently needed.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT on the outcome half of this entry's title. A larger single-centre series of 17 newly diagnosed SET-NUP214-positive acute leukaemias aged over 14 reports 16 of 17 achieving complete remission, including 12 of 13 T-ALL, with median overall survival 23 months and median relapse-free survival 21 months; 11 went to allogeneic transplant with median OS 37.5 months. Early chemotherapy resistance is not what that series shows. The two studies are not straightforwardly comparable - this one is newly diagnosed and unselected, the transplant series is CR1 transplants only and therefore conditions on having responded - and that is the point: 'resistant to steroids and chemotherapy early' is not established by a post-transplant relapse rate. Song Y et al. 2023
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
siRNA knockdown of SET-NUP214 in LOUCY induced differentiation, read out by flow cytometry as the percentage of cells positive for TCRgamma-delta and for membrane CD3 six days after electroporation, alongside abolished HOXA expression and inhibited proliferation; the effect was not reproduced in other T-ALL lines.
The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. · Van Vlierberghe P, et al. · Blood 2008What this evidence cannot show
One cell line, transient siRNA by electroporation, differentiation read at a single timepoint by two surface markers. The antibody clones are not recorded here and brief rule 74 applies - a surface TCRgamma-delta readout is clone-dependent. Full text read via the PMC HTML route (PMC2343598).
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT, about replication rather than about the readout. The differentiation phenotype rests on the only fusion-positive line anyone has ever knocked down. MEGAL is the one available replicate and it behaves differently on the one pathway perturbation run in both: it expresses less SET-Nup214 than LOUCY, its CRM1 and SET-Nup214 binding at the HOX clusters is weaker and confined mainly to HOXA9, and its HOX-expression response to KPT-330 is milder - for a reason the authors state remains unknown. A fusion-dependent differentiation block shown in one of two fusion-positive lines, with the other untested by knockdown and known to differ, is not yet a property of the fusion. Oka M et al. 2019
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a 96-patient Chinese T-ALL series, SET-NUP214 fusions were present in 3 of 48 (6.3%) and CALM-AF10 in 0 of 48; the genetic markers most frequently associated with PHF6 mutation were NOTCH1 mutation (P = .003), SET-NUP214 rearrangement (P = .002) and JAK1 mutation (P = .005).
Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia. · Wang Q, et al. · Haematologica 2011What this evidence cannot show
Abstract-level for this beat. SET-NUP214 was found in THREE patients, so the P = .002 association with PHF6 rests on a handful of cases and no multiple-testing correction is described in the abstract. A mixed adult (59) and paediatric (37) series. The denominators differ across the markers reported (96 for PHF6 and NOTCH1, 48-49 for the fusions and JAK1), so the percentages are not directly comparable.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT against the lineage-restriction claim this item is cited under. The same SET::NUP214-plus-PHF6-plus-EZH2 lesion set has been reported in a patient with concurrent, clonally related ACUTE UNDIFFERENTIATED LEUKAEMIA in the marrow and T-lymphoblastic lymphoma in the mediastinum - two immunophenotypically distinct presentations of one clone, with the AUL arm lacking lineage-specific markers altogether. If the identical genotype can present as a marker-null leukaemia, a PHF6 co-mutation frequency measured inside a T-ALL series is evidence about who gets enrolled in T-ALL series, not evidence that the fusion fixes a gamma-delta T-lineage state. Wei Q et al. 2025
gamma-delta-restricted arrest; knockdown releases TCR-gamma-delta and CD3 expression
two mechanistically unrelated KMT2A-free HOXA-high fusions restricted to the same arrested cell state
a fusion-maintained differentiation block, released by fusion knockdown
- confers resistance to →Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast
corticosteroid resistance 91% versus 44% in GRAALL adults, P = .003