Oncofusion

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

IFNGR1 - the receptor the whole antigen-presentation mechanism runs through, and the one where low-dose interferon-gamma makes MLL-fusion leukaemia worse

also called IFN-gamma receptor 1 · IFN-gamma-R1 · CDw119 · CD119 · interferon gamma receptor alpha chain

IFNGR1 is the antenna a leukaemia cell uses to hear the immune system's main alarm signal, and hearing it normally makes the cell put out more identity cards. But in a mouse model of this exact fusion family, a quiet version of that same signal makes the leukaemia stem cells grow better rather than worse.

The same thing, for a scientist

IFNGR1 (UniProt **P15260**, INGR1_HUMAN, **489 aa**, primary gene name IFNGR1, no listed gene synonyms, CD antigen **CD119**) is the ligand-binding chain of the interferon-gamma receptor [E1]. It is load-bearing for this beat in a way easy to miss: **almost every class I result in the menin-inhibitor literature is an enhancement of IFN-gamma-induced expression rather than an effect of the drug alone** [E2]. Without an IFN-gamma signal reaching IFNGR1, the pharmacology has much less to act on. And the direction of that signal in this fusion family is not simple. PMID 37872214 reports that **low serum IFN-gamma correlates with a higher leukaemia-stem-cell fraction and greater relapse incidence**, that **IFNGR1 is overexpressed in relapsed AML and associated with poor prognosis**, and - measured in an LSC-enriched **MLL-AF9** mouse model and in patient-derived AML LSCs - that **high-dose IFN-gamma is antileukaemic while low-dose IFN-gamma accelerates AML and supports LSC self-renewal**, with IFNGR1 knockdown or neutralisation inducing differentiation and delaying leukaemogenesis [E3].

Go deeper
A dose-inverted cytokine is a problem for every plan in this beat

The implicit model behind 'menin inhibition raises antigen presentation' is: more interferon signalling, more MHC, more T-cell killing. E3 says the input-output curve is non-monotonic in this fusion family, and that the low-dose arm - which is the arm a patient is likely to be on - runs the other way 3.

That matters in three concrete places:

  • The Fetsch mechanism 4 is HERV derepression producing interferon-stimulated gene upregulation. It is a type I interferon story rather than an IFN-gamma story, but the ISG output overlaps, and a chronic low-level interferon tone is precisely the regime E3 identifies as stem-cell-supporting.
  • The Sparbier and Hogeling class I effects both need IFN-gamma present to be large 2. Supplying it therapeutically is the obvious move and is the move E3 warns against at low dose.
  • A pharmacodynamic endpoint of 'MHC went up' is agnostic about which arm you are on. MHC rises under both doses in the published data; the leukaemia stem cell does not behave the same way.
What is and is not established for this fusion family

Established in an MLL-fusion model: the dose inversion, in MLL-AF9-driven LSCs, with IFNGR1 as the handle 3.

Not established anywhere: any IFNGR1 measurement in KMT2A-rearranged ALL; any IFNGR1 measurement in infant disease; any interaction between IFNGR1 signalling and a menin inhibitor. (KMT2A OR MLL) AND leukemia AND "interferon gamma"[tiab] returns 13 records and the plural-and-hyphen variant "IFN-gamma"[tiab] returns 10, with substantial overlap; none of them is about the index lymphoid disease 5.

And a baseline this graph already records as missing: cell-state-interferon-herv-mhc2 establishes that no baseline interferon or inflammatory-signature characterisation of KMT2A-rearranged leukaemia has been published. So the dose a patient's blasts actually see is unknown, and the sign of the effect depends on it.

Facts and figures
gene symbolIFNGR1
gene primaryIFNGR1
uniprotP15260
length AA489
uniprot entry nameINGR1_HUMAN
cd antigenCD119 (formerly CDw119)
cd number caseone gene - CD119 denotes IFNGR1 alone; but the functional receptor is IFNGR1(2)/IFNGR2(2), so a CD119 stain is not a measure of receptor competence
gene synonyms
[]
dose inversion
{
  "model": "LSC-enriched MLL-AF9 mouse; patient-derived AML LSCs",
  "high_dose": "5-10 micrograms/day, antileukaemic",
  "low_dose": "0.01-0.05 micrograms/day, accelerates AML and supports LSC self-renewal",
  "pmid": "37872214",
  "title": "Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.",
  "authors": "Xie X, Zhang W, Zhou X, et al.",
  "venue": "Oncogene",
  "year": 2023,
  "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."
}
counted absence
{
  "queries": [
    "(KMT2A OR MLL) AND leukemia AND \"interferon gamma\"[tiab]",
    "(KMT2A OR MLL) AND leukemia AND \"IFN-gamma\"[tiab]"
  ],
  "counts": [
    13,
    10
  ],
  "date": "2026-09-20",
  "gap": "no record concerns KMT2A-rearranged ALL or infant disease"
}
zhou locus set
{
  "IFNGR1": "Menin solo (chr6:137219384)",
  "JAK1": "Menin/H2AK119ub shared (chr1:64966548)",
  "source_pmid": "39158067",
  "join": "analyses/zhou-locus-set-join/results.json",
  "implication": "the interferon receptor and its kinase are both in menin's target set, so a menin inhibitor may change interferon RESPONSIVENESS as well as antigen presentation",
  "system_caveat": "adult myeloid KMT2A-r AML, gene-level, absence != unbound"
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": 0.1462,
  "chronos_mean_other_leukaemia": 0.1159,
  "difference": 0.0303,
  "pan_essentiality_all_lines": 0.0946,
  "selectivity_rank": 12892,
  "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
  • A menin inhibitor that raises interferon-stimulated genes chronically may be installing exactly the low-dose interferon tone that supports leukaemia-stem-cell self-renewal in this fusion family, while producing an antigen-presentation readout that looks like success.
  • The antigen-presentation benefit of menin inhibition is largely conditional on an interferon signal being present; in a lymphopenic, heavily pre-treated infant, and inside the CNS niche where this disease suppresses T-cell activity, that signal may be absent and the mechanism simply does not fire.
  • Supplying interferon-gamma therapeutically to make the mechanism work is the obvious combination and is the one the dose-inversion data warn about most directly.
  • IFNGR1 surface loss, or loss of IFNGR2, JAK1, JAK2 or STAT1, is the standard tumour escape from interferon-driven antigen presentation in other cancers and would be invisible to any MHC-transcript endpoint.
  • IFNGR1 and JAK1 are both in menin's target set, so the drug may be moving the interferon receptor and its kinase at the same time as it moves the antigen-presentation machinery - and the standard experiment, which co-stimulates with IFN-gamma, cannot separate the two.
Still open
  1. Does a menin inhibitor change IFN-gamma responsiveness itself? IFNGR1 is menin-solo and JAK1 is menin/H2AK119ub-shared in Zhou's target set, and every published class I result in this beat is measured as enhancement of IFN-gamma-INDUCED expression - so a shift in receptor or kinase level would be confounded with the effect it is used to demonstrate.
  2. What interferon dose do KMT2A-rearranged blasts actually see in marrow, and where on the non-monotonic curve does a menin inhibitor put them? This is measurable in xenograft marrow and has never been measured.
  3. Is the dose inversion a property of MLL-AF9 myeloid LSCs or of leukaemia stem cells generally? If it holds in KMT2A::AFF1 B-ALL, then any interferon-raising strategy in infants is a stem-cell-supporting strategy at the doses achievable.
  4. Does combining a menin inhibitor with exogenous high-dose IFN-gamma push past the stem-cell-supporting range into the antileukaemic one, and is that tolerable in an infant? The in vitro data say the combination should be strongly synergistic for MHC; the in vivo dose-response says the sign depends on getting the dose high enough.
Every source behind this entry (6)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The reviewed human UniProt record for interferon gamma receptor 1 is P15260 (INGR1_HUMAN), primary gene name IFNGR1, no listed gene synonyms, 489 aa, protein name 'Interferon gamma receptor 1' with alternative names IFN-gamma-R1, CDw119 and interferon gamma receptor alpha-chain, CD antigen CD119.

    UniProtKB reviewed human entry P15260 (INGR1_HUMAN) · UniProt Consortium · UniProtKB 2026
    What this evidence cannot show

    Database fact, fetched 2026-09-20 with gene_primary and length read back. Note the CD number: CD119 and the older CDw119 both denote this chain, and rule 69 applies - a source saying CD119 is saying IFNGR1, which is the one-gene case, but the functional receptor is a heterotetramer of two IFNGR1 and two IFNGR2 chains, so a CD119 flow measurement reports the ligand-binding chain and not receptor competence.

    Evidence that argues against this (1)
    • IFNGR1 surface expression does not equal IFN-gamma responsiveness: signalling requires IFNGR2 and intact JAK1/JAK2 and STAT1 downstream, and loss anywhere in that chain produces an IFNGR1-positive, interferon-unresponsive cell. A CD119 measurement is therefore not a measurement of the pathway this beat cares about. Chen BR et al. 2021
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In both published menin-inhibitor class I experiments the drug effect on surface MHC class I is predominantly an enhancement of interferon-gamma-induced expression: VTP50469 activated MHC-I gene expression dose-dependently and enhanced IFN-gamma-induced MHC-I protein, the validation experiments required 10-25 ng/mL IFN-gamma because that range gave more reliable HLA-B induction than the 1 ng/mL used in the screens, and the SCLC and neuroblastoma results are reported as increases in IFN-gamma-induced cell-surface MHC-I.

    Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes. · Sparbier CE, Gillespie A, Gomez J, Kumari N, Motazedian A, Chan KL, et al., Dawson MA · Nat Cell Biol 2023
    PMID 36635503DOI
    What this evidence cannot show

    This is an observation about experimental design as much as about biology: the system was built to be a sensitive screening readout, which is a reason to use cytokine co-stimulation, so the dependence on IFN-gamma in vitro is partly a property of the assay. The paper does report a dose-dependent drug-alone effect on MHC-I gene expression, so the dependence is quantitative rather than absolute. Read: full text (PMC7614190), 2026-09-20.

    Evidence that argues against this (1)
    • Hogeling's primary-AML class I result was obtained without exogenous interferon - four-day drug treatment alone raised HLA-A mRNA and surface MHC class I in 9 of 25 samples - so the drug can move class I without added cytokine in patient material. Whether endogenous interferon in those cultures supplied the signal is not addressed. Hogeling SM et al. 2025
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Low serum interferon-gamma correlated with a higher percentage of leukaemia stem cells and greater relapse incidence in AML patients; IFNGR1 was overexpressed in relapsed AML and associated with poor prognosis; high doses of IFN-gamma (5-10 micrograms/day) were antileukaemic while low doses (0.01-0.05 micrograms/day) accelerated AML development and supported leukaemia-stem-cell self-renewal in patient-derived AML LSCs and in an LSC-enriched MLL-AF9-driven mouse model; and targeting IFNGR1 with lentiviral shRNA or neutralising antibodies induced AML differentiation and delayed leukaemogenesis in vitro and in mice.

    Low doses of IFN-gamma maintain self-renewal of leukemia stem cells in acute myeloid leukemia. · Xie X, Zhang W, Zhou X, Xu B, Wang H, Qiu Y, et al. · Oncogene 2023
    PMID 37872214DOI
    What this evidence cannot show

    Murine MLL-AF9 and patient-derived AML LSCs; myeloid throughout, with no lymphoid or infant arm. The dose figures are administered doses in mice and do not translate to a concentration at the blast in a patient. The human data are correlative - serum cytokine against LSC fraction and outcome - and serum IFN-gamma is a poor proxy for marrow microenvironment concentration. No menin inhibitor anywhere in the paper. Read: abstract only; record and identifiers fetched 2026-09-20.

    Evidence that argues against this (1)
    • The opposite direction is equally well published in this fusion family: menin inhibition raising interferon-stimulated genes improves graft-versus-leukaemia and donor T-cell effector function in KMT2A-rearranged AML models (PMID 41144759), and IFN-gamma production by T cells is the readout of successful killing in both menin-inhibitor class I experiments. The reconciliation is presumably dose and cell compartment - interferon acting on the T cell versus on the blast - but no experiment in this literature separates them. Fetsch V et al. 2026
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Menin inhibition increased expression of multiple human endogenous retroviruses leading to consecutive interferon-stimulated gene upregulation and enhanced MHC class II in KMT2A-rearranged and NPM1-mutated AML.

    Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML. · Fetsch V, Schwobel L, Ozyerli-Goknar E, Stell AV, Punta M, Plenge T, et al., Zeiser R · Blood 2026
    PMID 41144759DOI
    What this evidence cannot show

    Cited to establish that a menin inhibitor raises interferon tone in this disease, which is the input to the dose question E3 raises. This is a type I interferon (HERV/dsRNA) route, not an IFN-gamma route, so it does not act through IFNGR1; the overlap is at the level of interferon-stimulated gene output. AML only. Read: abstract only.

    Evidence that argues against this (1)
    • If chronic low-level interferon tone supports leukaemia-stem-cell self-renewal (PMID 37872214), then a drug that raises interferon-stimulated genes persistently could be creating the stem-cell-supporting regime while producing an impressive antigen-presentation pharmacodynamic. No published experiment measures LSC frequency and MHC together under a menin inhibitor. Xie X et al. 2023
  5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    As of 2026-09-20, `(KMT2A OR MLL) AND leukemia AND "interferon gamma"[tiab]` returns 13 PubMed records and `(KMT2A OR MLL) AND leukemia AND "IFN-gamma"[tiab]` returns 10, with substantial overlap, and no record in either set characterises interferon-gamma biology in KMT2A-rearranged acute lymphoblastic leukaemia or in infant disease.

    What this evidence cannot show

    Bounded absence. Both the spelled-out and the abbreviated hyphenated forms were run because PubMed matches multi-word tiab terms as unstemmed phrases (the rule that cost an earlier beat a wrong counter-evidence claim). NOT searched: 'IFNgamma' unspaced, the Greek-letter form, 'type II interferon', or IFNGR1/IFNGR2 as symbols. The judgement that none concerns the lymphoid index disease is a title-level judgement over 23 records with overlap, not a full-text review.

    Evidence that argues against this (1)
    • The count is not zero and includes on-topic myeloid work, so this is a gap in a specific population rather than an untouched field; treating it as 'nobody has studied interferon in MLL leukaemia' would be wrong in the way rule 64 describes. Xie X et al. 2023
  6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In Zhou's published menin and H2AK119ub target set from KMT2A-rearranged AML, IFNGR1 falls in the MENIN-SOLO group at chr6:137219384 - menin-bound without H2AK119ub - and JAK1, the kinase immediately downstream of it, falls in the MENIN/H2AK119ub-SHARED group at chr1:64966548.

    Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia. · Zhou X, Zhang L, Aryal S, Veasey V, Tajik A, Restelli C, Moreira S, Zhang P, et al. · Blood 2024
    PMID 39158067DOI
    What this evidence cannot show

    Bounded by the source system: Zhou's locus set is KMT2A-rearranged ADULT MYELOID AML, largely OCI-AML2 (CVCL_1619, KMT2A::AFDN) and MV4-11 plus mouse models, not infant B-lineage KMT2A::AFF1. The intervals are 2 bp TSS anchor points carrying a gene id, so this supports a GENE-LEVEL intersection and not a base-resolution one. Most important: ABSENCE FROM THE TABLE IS NOT ABSENCE OF BINDING - it is absence from Zhou's called set under Zhou's thresholds in Zhou's cells. Symbol-to-ENSG resolution refuses any symbol mapping to more than one ENSG, which is why HLA-A, HLA-B, HLA-DRA, HLA-DRB1 and B2M are all unresolved in this join and the class I layer is invisible to it. Join run 2026-09-20; the Zhou PubMed record and DOI were fetched independently by this beat rather than copied. Zhou's paper does not discuss IFNGR1 or JAK1; these are the join's readout of its supplementary Table 4. An occupancy call is not a functional result and says nothing about the direction or size of any expression change under a menin inhibitor.

    Evidence that argues against this (1)
    • If the receptor and the kinase carrying the interferon signal are themselves menin-bound, a menin inhibitor could alter the cell's interferon RESPONSIVENESS as well as its antigen presentation, in an unknown direction - and every published class I result in this beat is an enhancement of IFN-gamma-INDUCED expression, so a change in responsiveness would be confounded with the antigen-presentation effect in exactly the experiments used to demonstrate it. No published experiment measures IFNGR1 or JAK1 under a menin inhibitor. Sparbier CE et al. 2023
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