Oncofusion

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Cell typemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q54-immune

The NK cell - the effector arm of haploidentical transplant, the one this disease is documented to evade, and the cell CLEC12A was named on

also called natural killer cell · NK cells · CD56+ CD3- lymphocyte · innate lymphocyte

NK cells kill cells that look wrong without needing to be trained first, and they are the main reason a mismatched bone-marrow transplant can cure leukaemia. This disease has three documented ways of hiding from them, and almost nothing in this graph was about them until now.

The same thing, for a scientist

NK cells are the innate cytotoxic lymphocytes whose activity is set by the balance of inhibitory receptors reading MHC class I - KIR in humans, Ly49 in mice - against activating receptors, chiefly NKG2D reading stress ligands. They matter to this project for four reasons that this graph has been carrying separately without a cell entry to hang them on. **They are the effector arm of haploidentical and KIR-mismatched transplantation**, the strategy behind a durable remission in a relapsed infant KMT2A-rearranged case [E4]. **This disease evades them in three documented layers** - inhibitory KIR ligands present, NKG2D activating ligands and adhesion molecules low, and protease inhibitor-9 blocking granzyme B downstream [E1]. **A classical class I molecule is an NK-dependent in vivo dependency of MLL-AF9 leukaemia-initiating cells** [E2]. And **NK-resistant variants are selected during leukaemia development** in an immunocompetent host [E3]. Meanwhile `gene-clec12a` - the antigen behind the failed CLL-1 CAR trial and the target a menin inhibitor is reported to induce - is itself an **inhibitory C-type lectin-like receptor of the NK-gene complex**, which is the reason its aliases include KLRL1.

Go deeper
Why an NK entry and not a T-cell entry

This graph already carries cell-type-car-cell and a T-cell-heavy immunotherapy layer. It had no NK entry at all, while carrying: a CLEC12A dossier whose gene sits in the NK gene complex; a haploidentical-transplant concept entry; three immunotherapy failures; and an interferon/GVL cell state. The NK cell is the connecting node for all of them and its absence is why the class I trade-off in risk-raising-mhc-class-i-trades-t-cell-visibility-for-nk-inhibition had never been noticed.

And the age argument is specific. NK cells are the dominant cytotoxic lymphocyte population in early infancy, when the adaptive compartment is immature and KIR repertoires are still being established. The index disease is a disease of infants. Every NK result cited here is from adult or murine material.

The activating side is unsettled and it decides the newest strategy

Two papers, fourteen years apart, point in different directions on NKG2D ligands in this disease:

  • Chan 2012: three KMT2A-rearranged lines express low NKG2D activating ligands 1.
  • Ren 2026: the superiority of bispecific CD19-CD133 CAR-iNKT cells over CAR T cells against KMT2A-rearranged ALL is mediated by CAR-dependent upregulation of NKG2D on the effector and its engagement by NKG2D ligands on the KMT2Ar-ALL cells, which is what preserves killing when CD19 or CD133 is downregulated 5.
  • Nakata 2014: in the MLL/ENL model, upregulation of NKG2D ligands on leukaemia cells is what causes NK-mediated elimination, and NK-resistant cells are selected 3.

Both can be true - low is not absent, and an effector with high NKG2D may engage a low ligand density. But the graph should not assert a settled NKG2D-ligand level in KMT2A-rearranged leukaemia, and the CAR-iNKT rationale depends on a quantity nobody has measured across a patient cohort.

CLEC12A is an NK-complex receptor, which is a fact about the target, not only about the drug

gene-clec12a records CLEC12A/CD371/CLL-1/MICL as an inhibitory C-type lectin-like receptor on myeloid cells. Its alias KLRL1 - killer cell lectin-like receptor L1 - names the family and the locus: the NK gene complex on 12p13, alongside NKG2D, NKG2A and the CD94 family.

Three consequences worth recording once, here:

  • A CLEC12A-directed CAR engages a receptor whose physiological job is inhibitory signalling, so the target is not an inert flag.
  • A menin inhibitor reported to induce CLEC12A 6 is inducing an inhibitory receptor on the leukaemic cell, and what that does to the cell's own signalling has not been asked - only what it does to CAR binding.
  • The KITE-222 CLL-1 CAR trial failed through persistence of CLL-1-negative blasts 7, which is antigen heterogeneity and not an NK phenomenon; naming it here keeps the two failure modes apart.

This entry does not restate the CLEC12A dossier. It records that the antigen belongs to the NK receptor family and that the graph had no place to say so.

Facts and figures
ontologyCL:0000623
locationbone marrow, blood, and the graft in allogeneic transplantation
clec12a is an nk complex geneCLEC12A/CD371/CLL-1/MICL, alias KLRL1 - killer cell lectin-like receptor L1, NK gene complex at 12p13; an inhibitory receptor, not an inert surface flag
age gapNK cells are the dominant cytotoxic lymphocyte population in early infancy and KIR repertoires are still maturing; every NK result cited here is adult or murine
markers
[
  "CD56",
  "CD16",
  "CD3-negative",
  "NKp46",
  "NKG2D"
]
receptor logic
{
  "inhibitory": "KIR (human, reading HLA-A Bw4 / HLA-B Bw4 / HLA-C C1 and C2 groups), NKG2A (reading HLA-E), Ly49 (murine)",
  "activating": "NKG2D reading MICA/MICB and ULBP stress ligands"
}
evasion layers documented in this disease
[
  "inhibitory KIR ligands present (PMID 23014531)",
  "NKG2D activating ligands and adhesion molecules low (PMID 23014531)",
  "protease inhibitor-9 / serpin B9 blocking granzyme B downstream of recognition (PMID 23014531)",
  "selection of NK-resistant variants during leukaemogenesis (PMID 24336127)"
]
How this could bite us back
  • Any strategy that raises MHC class I strengthens the inhibitory input to this cell, and in this fusion family a class I molecule is an NK-dependent in vivo leukaemia dependency.
  • NK-resistant variants are selected during leukaemogenesis, so an established leukaemia has already defeated this arm once.
  • Protease inhibitor-9 blocks granzyme B inside the target cell and defeats NK and T-cell killing alike after recognition; no strategy in this beat addresses it.
  • CLEC12A-directed therapy ablates normal myeloid cells (see `risk-clec12a-directed-therapy-myeloid-ablation`), and a menin inhibitor that induces CLEC12A would be expected to induce it on normal myeloid cells too - the same target-creation mechanism, applied to the wrong cells.
Still open
  1. What is the NKG2D ligand density on primary KMT2A-rearranged infant blasts? Two papers give opposite impressions and the newest therapeutic strategy in this disease depends on the answer.
  2. Does inducing CLEC12A with a menin inhibitor change the blast's own inhibitory signalling, as opposed to changing how much CAR binds it? CLEC12A is an ITIM-bearing inhibitory receptor and nobody has asked what inducing it does to the cell that now carries it.
  3. Is there a registry denominator for KIR-ligand-mismatched transplantation in KMT2A-rearranged childhood leukaemia? One case report is not evidence and the data exist in transplant registries.
  4. Does infant NK biology change the calculus? The disease is an infant disease and the NK compartment at that age is not the adult one.
Every source behind this entry (7)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Three MLL-rearranged leukaemia cell lines (RS4;11, SEM, MV4-11) and primary blasts were resistant to NK-cell lysis, had inhibitory KIR ligands and protease inhibitor-9 and expressed low levels of NKG2D activating ligands and adhesion molecules; anti-CD19 or anti-CD33 antibody treatment made them efficiently killed by NK cells, and blocking the inhibitory KIR-HLA interaction with a pan-MHC class I antibody further augmented degranulation in every KIR subset.

    PMID 23014531DOI
    What this evidence cannot show

    All three lines are t(4;11) KMT2A::AFF1, so the genotype is narrow; in vitro assays with a xenograft survival arm; 2012, with no modern replication found. 'Some inhibitory KIR ligands' is the authors' hedge. Read: abstract only; identifiers fetched 2026-09-20.

    Evidence that argues against this (1)
    • The paper's own conclusion is that the answer is an antibody against a leukaemia antigen plus KIR-mismatched NK transplantation plus KIR blockade - a triple approach - which concedes that NK cells alone do not control this disease and that MHC-independent engagement is doing most of the work. Chan WK et al. 2012
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    H2-k1, a classical MHC class I molecule, is a top in vivo dependency of MLL-AF9 leukaemia-initiating cells; its loss depletes leukaemia in vivo and extends survival, and the effect is completely rescued by NK-cell depletion but unaffected by macrophage depletion.

    H2-K1 protects murine MLL-AF9 leukemia stem cells from natural killer cell-mediated immune surveillance. · Ghosh S, Rodriguez-Zabala M, Dushime GT, Reinbach K, Ramakrishnan R, Sitnicka E, Jaras M · Haematologica 2025
    PMID 39844759DOI
    What this evidence cannot show

    Murine MLL-AF9, myeloid; the human arm is an expression comparison only. Read: full text via the PMC HTML page (PMC12130766) after the PubMed abstract field came back empty.

    Evidence that argues against this (1)
    • NK function is independently documented as impaired in AML patients, and patients on these drugs are frequently lymphopenic or immunosuppressed, so an NK-dependent effect measured in an immunocompetent mouse may not have a counterpart in the clinic. Ghosh S et al. 2025
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    MLL/ENL leukaemia cells were rejected in immunocompetent mice without preconditioning and in 60% of Rag2-/- mice retaining NK cells, while all Rag2-/-gc-/- mice lacking NK cells developed leukaemia; NK depletion enhanced and NK transfer inhibited engraftment; upregulation of NKG2D ligands caused NK-mediated elimination; and NK-resistant leukaemia cells were selected during leukaemia development.

    In vivo eradication of MLL/ENL leukemia cells by NK cells in the absence of adaptive immunity. · Nakata J, Nakano K, Okumura A, Mizutani Y, Kinoshita H, Iwai M, et al. · Leukemia 2014
    PMID 24336127DOI
    What this evidence cannot show

    Murine MLL-ENL, myeloid, no conditioning - a stringent immunosurveillance design whose transfer to established human disease is limited. The selection result is reported without molecular characterisation. Read: abstract only; identifiers fetched 2026-09-20.

    Evidence that argues against this (1)
    • If NK-resistant variants are selected during leukaemogenesis, then by the time a patient is diagnosed the NK axis has already been defeated, and NK-based therapy is attempting to reverse an escape rather than to prevent one. That is a harder problem and may explain the gap between preclinical promise and clinical results. Nakata J et al. 2014
  4. E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    A patient with KMT2A-rearranged infant acute lymphoblastic leukaemia who relapsed in marrow and central nervous system after HLA-matched cord blood transplantation was retransplanted in second remission with KIR-ligand-mismatched cord blood under reduced-intensity conditioning and remained in remission at 52 months.

    PMID 36706271DOI
    What this evidence cannot show

    Single case report, n=1, with conditioning intensity and graft source confounded with the KIR-ligand mismatch; publication bias for single durable remissions is total. Recorded because it is the only clinical application of missing-self logic in this disease found by this beat. Read: abstract only.

    Evidence that argues against this (1)
    • No denominator exists. How many KMT2A-rearranged children have received KIR-ligand-mismatched grafts, and with what outcomes, is a registry question that this beat could not answer from the literature. Mizuki K et al. 2023
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Bispecific CD19-CD133 CAR-iNKT cells eradicated medullary and leptomeningeal KMT2A-rearranged ALL in preclinical models and outperformed CAR T cells, with the mechanism identified as CAR-dependent and CAR-antigen-dependent upregulation of NKG2D on the CAR-iNKT cells and its engagement by NKG2D ligands on the KMT2A-rearranged ALL cells, preserving killing of antigen-low leukaemia.

    Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk KMT2A-rearranged leukemia. · Ren H, Elliott N, Lye B, Sharif Shohan MU, Cross JW, Field L, et al. · Blood 2026
    PMID 40898981DOI
    What this evidence cannot show

    Preclinical only. iNKT cells are a distinct lineage from conventional NK cells - CD1d-restricted T cells with innate features - so this is cited for the NKG2D-ligand observation on KMT2A-rearranged ALL cells, which is the only such measurement in the index disease and lineage that this beat found, and not as an NK-cell result. Read: abstract only; identifiers fetched 2026-09-20.

    Evidence that argues against this (1)
    • It sits in tension with the 2012 report of LOW NKG2D ligands on KMT2A-rearranged lines. Neither paper measures ligand density across a patient cohort, so the strategy's key premise is supported by a mechanism sub-experiment in one preclinical study. Chan WK et al. 2012
  6. E6weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

    A 2026 preprint reports that menin inhibition induces robust and uniform CLEC12A expression in KMT2A-rearranged and NPM1-mutated AML, that menin inhibitors do not impair T- or NK-cell viability, phenotype or effector function, and that CLEC12A-directed CAR T cells combined with menin inhibition outperform either monotherapy in vitro and in xenografts.

    DOI
    What this evidence cannot show

    Preprint, not peer reviewed. The identifier and framing are taken from this graph's existing `mechanism-menin-inhibition-induces-clec12a`, which is the entry that owns this source; it is cited here only for the statement that menin inhibitors do not impair NK-cell viability or effector function, which is the single published datum bearing on whether a menin inhibitor harms the NK compartment. This beat did not independently verify the preprint's contents beyond the identifier, and the DOI prefix is non-standard - see `ana-the-preprint-discipline-holds-and-the-trap-is-the-doi-prefix`.

    Evidence that argues against this (1)
    • 'Does not impair NK cells' is a statement about the effector; the concern in this beat is about the target - that a menin inhibitor raises the inhibitory class I ligand on the blast. A preprint showing intact NK function in the presence of the drug does not address whether the blast has become harder for those intact NK cells to kill. Ghosh S et al. 2025
  7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In a phase 1 study of KITE-222, an autologous CLL-1-directed CAR T-cell therapy in relapsed or refractory acute myeloid leukaemia, no clinically meaningful responses were achieved, with persistence of CLL-1-negative blasts after clearance of CLL-1-positive blasts.

    Phase 1 Study of KITE-222, an Autologous CLL-1-Directed CAR T-cell Therapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. · Daver N, Blachly JS, Ghobadi A, Advani A, Muffly L, Garciaz S, et al. · Clin Cancer Res 2026
    PMID 41941266DOI
    What this evidence cannot show

    Cited to keep two failure modes distinct: this is antigen heterogeneity, not NK evasion. The full analysis of this trial belongs to `gene-clec12a` and `mechanism-menin-inhibition-induces-clec12a`. Read: PubMed record and identifiers fetched 2026-09-20; the content statement is the one this graph already records, with identifiers re-fetched rather than copied.

    Evidence that argues against this (1)
    • A CAR trial failing on antigen heterogeneity says nothing about NK biology, and citing it in an NK entry risks exactly the conflation this section exists to prevent. It is included only as the negative boundary of the CLEC12A story. Jin X et al. 2022
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