GenemoderateQ54-immunedisputed

CIITA - the class II transactivator, a gene menin sits on, and the only antigen-presentation gene in this disease with a knockout that proves the drug acts through it

also called MHC2TA · C2TA · MHC class II transactivator · class II transactivator

CIITA is the master switch for the second kind of identity card leukaemia cells show to immune cells. Menin sits on the CIITA gene, and when a menin inhibitor is added the switch turns on - and deleting CIITA stops the drug working on that card entirely.

The same thing, for a scientist

CIITA (UniProt **P33076**, C2TA_HUMAN, **1,130 aa**, primary gene name CIITA, synonym MHC2TA) is the non-DNA-binding master transactivator of MHC class II [E1]. It belongs in an antigen-presentation beat centred on class I because it supplies the **control experiment class I does not have**. In primary AML and MV4-11, bleximenib raised CIITA mRNA, **menin binding at the CIITA and HLA-DR loci was reported by ChIP-qPCR** (contested - a genome-wide locus set places CIITA in the polycomb-marked, menin-unbound group; see the CONTESTED section), and HLA-DR induction by the drug was **abolished in CIITA-null MV4-11 cells** and reduced in heterozygotes [E2]. That is a genetic demonstration that the menin-KMT2A complex controls class II *through* CIITA. There is no equivalent experiment for class I anywhere in this literature, and NLRC5 - CIITA's class I counterpart - has never been tested under a menin inhibitor in any system. Separately, **common subunits of the MLL/COMPASS complexes bind the cytokine-inducible CIITA pIV and MHC-II promoters and are required for H3K4me3 there**, with H3K27me3 moving inversely [E3], which is the oldest and least-cited link between the KMT2A family and antigen presentation.

Go deeper

Why the CIITA knockout matters to a class I beat

Three papers now say a menin inhibitor raises MHC. They attribute it to three different things:

source	arm	proposed route	genetic test
PMID 39704147	class II	CIITA	yes - CIITA-null MV4-11 loses the induction 2
PMID 41144759	class II	HERV derepression, interferon-stimulated genes	not reported in the abstract
PMID 36635503	class I	polycomb-KMT2A rebalancing; explicitly not STAT1, not MDA-5, not RELA	epistasis with MEN1/PSIP1 and KMT2A/B knockouts

Only the CIITA arm has a clean loss-of-function proof. And CIITA's own regulation is the reason the two class II papers can both be right - CIITA pIV is interferon-inducible, so a HERV-driven interferon response and a direct chromatin effect at the CIITA locus converge on the same transactivator.

For class I the corresponding gene is NLRC5 and the corresponding experiment does not exist. Writing that down is the point of this entry.

The 2010 result nobody has followed up

PMID 20181089 predates all of this by fifteen years. It reports that multiple common subunits of the MLL/COMPASS complexes bind the inducible MHC-II and CIITA promoters, that overexpressing a single common subunit significantly enhances promoter activity and HLA-DRA expression, and that those subunits are required for H3K4me3 at both promoters; H3K27me3, inversely correlated, rose when the 19S ATPase Sug1 was diminished 3.

That is a bivalency-shaped result at CIITA, from a laboratory studying proteasomal control of transcription, with no leukaemia in it. This graph already cites it once, in target-hla-dr-class-ii-heterodimer. It is worth restating here because it establishes the direction the KMT2A family acts in at these promoters - as an activator - which is the direction Sparbier's KMT2A/KMT2B knockout later confirmed for class I 4. A menin inhibitor that removes KMT2A from active genes and redistributes it is therefore acting on a system where the family's baseline role at antigen-presentation promoters was already known to be positive.

Caution on attribution. 'Common MLL/COMPASS subunits' means WRAD and friends - shared across KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B. The paper does not attribute the effect to KMT2A specifically, and this graph's concept-kmt2-family-attribution-problem is the standing warning against reading a COMPASS result as a KMT2A result.

CONTESTED (added after the Zhou join): is menin actually at the CIITA locus?

This entry's E2 carries Hogeling's ChIP-qPCR result: menin binding confirmed at the CIITA and HLA-DR loci, with HLA-DR induction lost in CIITA-null MV4-11. A genome-wide intersection now points the other way.

In Zhou's published 9,292-locus menin/H2AK119ub target set from KMT2A-rearranged AML, CIITA is in the H2AK119ub-SOLO group - polycomb-marked and menin-unbound 5.

	Hogeling (PMID 39704147)	Zhou locus set (PMID 39158067)
method	targeted ChIP-qPCR at a chosen amplicon	genome-wide called set, thresholded
cells	MV4-11 (KMT2A::AFF1)	largely OCI-AML2 (KMT2A::AFDN) and MV4-11
verdict at CIITA	menin bound	menin absent, H2AK119ub present

Neither is obviously wrong. A thresholded genome-wide caller can miss a modest real peak; a targeted qPCR at one amplicon can report occupancy a caller would not credit. And Zhou's own caveat applies - absence from the table is absence from the called set, not demonstrated absence of binding.

What changes, and what does not. The functional claim is untouched: CIITA-null MV4-11 loses the drug's HLA-DR induction, so the effect runs through CIITA whether or not menin sits on it 2. What is now contested is the directness - whether menin inhibition raises CIITA by vacating the CIITA locus, or indirectly, as Fetsch's HERV-to-interferon route would predict 4. The Zhou row is evidence for the indirect reading, and it agrees with the class I side of this beat, where menin is likewise not bound at bivalent MHC-I promoters.

And a second row in the same table cuts the other way for class I. NLRC5 - the class I transactivator - is in the MENIN-SOLO group 5. So in Zhou's system the class II transactivator is polycomb-marked and menin-free while the class I transactivator is a direct menin target. If that holds, the two arms are not merely different mechanisms (mechanism-class-i-derepression-under-menin-inhibition-is-not-viral-mimicry) but opposite ones: class II indirect, class I potentially direct through NLRC5. Nobody has tested it.

Facts and figures

gene symbol	CIITA
gene primary	CIITA
uniprot	P33076
length AA	1130
uniprot entry name	C2TA_HUMAN
class i counterpart	NLRC5 (Q86WI3) - never tested under a menin inhibitor in any system
menin occupancy	CONTESTED. PMID 39704147 reports ChIP-qPCR-confirmed menin binding at the CIITA and HLA-DR loci. Zhou's genome-wide 9,292-locus set (PMID 39158067) places CIITA in the H2AK119ub-SOLO group - polycomb-marked, menin-unbound - at chr16:10877200. The functional CIITA dependence of the drug effect is not in dispute; the DIRECTNESS is. Contrast with class I, where menin ChIP-seq found no binding at bivalent MHC-I promoters (PMID 36635503), and with NLRC5, which Zhou places in the MENIN-SOLO group.
contamination register	CIITA is also a recurrent fusion partner in lymphoid malignancy (e.g. IKZF1::CIITA, PMID 40899517); a CIITA hit may be a rearrangement, not a transactivator finding
subnuclear localization	unpublished - CIITA has no subnuclear compartment in any source read for this beat; what is published is a nucleocytoplasmic partition and the import and export signals that set it (PMID 11564775).
shown for fusion	NO. CIITA's localisation has never been examined in a KMT2A-rearranged cell, and this is a load-bearing gap rather than a formality: this graph's CIITA entry turns on menin occupancy at the CIITA gene and on what a menin inhibitor does to MHC class II. Every one of those arguments is transcriptional, and a transcription factor whose activity is set by an import/export balance can be transcribed and still be inactive.

gene synonyms

[
  "MHC2TA"
]

genetic proof

{
  "system": "MV4-11 (KMT2A::AFF1) CIITA+/- and CIITA-/-",
  "drug": "JNJ-75276617",
  "result": "dose-dependent HLA-DR induction in scrambled, absent in CIITA-/-",
  "pmid": "39704147",
  "title": "Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia.",
  "authors": "Hogeling SM, Lê DM, La Rose N, et al.",
  "venue": "Haematologica",
  "year": 2025,
  "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."
}

zhou locus set

{
  "CIITA": "H2AK119ub solo (chr16:10877200)",
  "NLRC5": "Menin solo (chr16:56989555)",
  "source_pmid": "39158067",
  "join": "analyses/zhou-locus-set-join/results.json",
  "system_caveat": "adult myeloid KMT2A-r AML, gene-level, absence != unbound"
}

localization

{
  "subcellular": "BOTH nucleus and cytoplasm, and the balance is the regulated quantity - CIITA is a nucleocytoplasmic shuttling protein. Its steady-state distribution is set by at least two nuclear localisation signals (a C-terminal one whose deletion causes a form of type II bare lymphocyte syndrome, and a classical SV40-like 10-residue motif at residues 405-414) balanced against leptomycin-B-sensitive CRM1-dependent nuclear export. Deleting 405-414 puts CIITA in the cytoplasm and abolishes transactivation; replacing it with the SV40 NLS rescues both.",
  "subnuclear": "unpublished. No nuclear-body, speckle or other subnuclear compartment assignment for CIITA was located in any source read for this beat; the published spatial facts are entirely nuclear-versus-cytoplasmic partition and the signals that set it.",
  "how_shown": "sequential C-terminal deletion series, NLS transplantation onto a heterologous protein, NLS replacement rescue, and leptomycin B inhibition of export (PMID 11564775); the same authors state in that paper that deletion of the C-terminal NLS produces cytoplasmic CIITA and one form of type II bare lymphocyte syndrome",
  "systems": "transfected mammalian cells; the clinical precedent is a human bare lymphocyte syndrome patient. No leukaemic or KMT2A-rearranged system.",
  "node": "localization-partner-baseline-compartment-is-often-miscalled"
}

depmap kmt2a selectivity

{
  "chronos_mean_kmt2a_rearranged": 0.0686,
  "chronos_mean_other_leukaemia": 0.0473,
  "difference": 0.0213,
  "pan_essentiality_all_lines": 0.0418,
  "selectivity_rank": 11886,
  "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

Raising MHC class II is the graft-versus-host-disease substrate as much as the graft-versus-leukaemia substrate, and the post-transplant setting where this mechanism is proposed is also where class II mismatch causes the most harm.
CIITA loss is a documented lymphoma escape route and is cheap: one transactivator removes all class II at once, exactly as B2M removes all class I. Any therapy that works by raising class II selects for cells without the transactivator.
If the drug's class II effect depends on CIITA and the class I effect does not depend on NLRC5, then the two arms have different resistance genetics and a single 'MHC-high' pharmacodynamic endpoint would conflate them.
MV4-11 and the KMT2A-rearranged AML lines are myelomonocytic and express class II constitutively; an induction measured there may be a lineage property being amplified rather than a silenced gene being reawakened, and no lineage-matched control is reported.
A menin inhibitor is argued in this graph to raise MHC class II through CIITA, and that argument is entirely transcriptional. CIITA activity requires nuclear residence set by an import/export balance (PMID 11564775), so raising CIITA message need not raise CIITA function - and because export is leptomycin-B-sensitive and therefore CRM1-dependent, an XPO1 inhibitor would be predicted to raise nuclear CIITA without touching its transcription. Neither prediction has been tested in KMT2A-rearranged cells, and they are cheap to test together.

Still open

Is menin actually at the CIITA locus? A targeted ChIP-qPCR says yes in MV4-11 and a genome-wide called set says no in a KMT2A::AFDN-dominated system. One menin CUT&RUN in a KMT2A::AFF1 line with the CIITA amplicon read out explicitly would settle a disagreement that currently decides whether the class II effect is direct or indirect.
Is there an NLRC5 knockout experiment to match the CIITA one? The class II mechanism is proven by loss of function in a KMT2A-rearranged line; the class I mechanism is not, and the experiment is the same experiment with a different guide RNA.
Do the two proposed routes to CIITA - direct menin occupancy at the locus versus HERV-driven interferon acting on the inducible pIV promoter - operate together or is one an artefact of system? A CIITA promoter-usage assay under a menin inhibitor with and without JAK inhibition would separate them.
Does the 2010 COMPASS result at CIITA belong to KMT2A, to KMT2B, or to SETD1A/B? A paralogue-resolved degron experiment at the CIITA locus is a small, self-contained project that would settle a fifteen-year-old attribution.

Every source behind this entry (6)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The reviewed human UniProt record for the MHC class II transactivator is P33076 (C2TA_HUMAN), primary gene name CIITA, synonym MHC2TA, 1,130 aa, protein name 'MHC class II transactivator'.
UniProtKB reviewed human entry P33076 (C2TA_HUMAN) · UniProt Consortium · UniProtKB 2026
What this evidence cannot show
Database fact, fetched 2026-09-20, gene_primary read back per rule 62. Single reviewed record; 1,130 aa discriminates cleanly. Note that CIITA is a recurrent fusion partner in lymphoid malignancy - this beat found IKZF1::CIITA reported in a B-ALL RNA-sequencing series (PMID 40899517) - so a CIITA hit in a leukaemia paper may be about a rearrangement rather than about transactivator function.
Evidence that argues against this (1)
- A CIITA token search in leukaemia is contaminated by the fusion-partner register: `(KMT2A OR MLL) AND leukemia AND CIITA[tiab]` returns 3 records, of which one is a targeted RNA-sequencing panel study reporting an IKZF1::CIITA fusion and nothing about antigen presentation. Two of three on-topic is an unusually clean ratio for this beat but the contamination class is real. Q54-immune et al. 2026
E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In primary AML and AML cell lines, the menin-KMT2A inhibitor JNJ-75276617 raised CIITA mRNA with a strong positive correlation between the fold change in CIITA and in HLA-DR (R-squared 0.748); menin binding at the CIITA and HLA-DR loci was confirmed by ChIP-qPCR; HLA-DR expression was significantly lower at baseline in CIITA heterozygous and homozygous knockout MV4-11 cells than in scrambled controls, and dose-dependent HLA-DR upregulation on treatment occurred in scrambled but not in CIITA-null cells; the effect was MEIS1-independent, with no correlation between MEIS1 and HLA-DR fold changes and HLA-DR still upregulated in MEIS1-overexpressing cells.
Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia. · Hogeling SM, Le DM, La Rose N, Kwon MC, Wierenga ATJ, Van den Heuvel FAJ, et al., Schuringa JJ · Haematologica 2025
PMID 39704147 DOI
What this evidence cannot show
The CIITA knockout was made in MV4-11, which is KMT2A::AFF1-rearranged - so this is, narrowly, the one genetic antigen-presentation experiment in this beat performed in a KMT2A-rearranged cell, and it is about class II, not class I. It is a cell-line result with no primary-sample replication of the knockout. MV4-11 is a myelomonocytic line and monocytic cells express class II constitutively, which is a lineage background the experiment does not control for. Read: full text via the PMC HTML route (PMC12130779), 2026-09-20.
Evidence that argues against this (1)
- The same paper shows CIITA-driven class II induction is not sufficient for immune benefit: sample AML54 gained strong HLA-DR and no HLA-A, and T-cell cytotoxicity was not enhanced. A proven mechanism for raising the molecule is not a proven mechanism for killing the cell. Hogeling SM et al. 2025
E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Multiple common subunits of the MLL/COMPASS complexes bind the cytokine-inducible MHC class II and CIITA promoters; overexpressing a single common MLL/COMPASS subunit significantly enhanced promoter activity and MHC-II HLA-DRA expression; those subunits are required for H3K4 trimethylation at the MHC-II and CIITA promoters; and H3K27 trimethylation, inversely correlated with H3K4me3, was significantly elevated when the 19S ATPase Sug1 was diminished.
Roles for common MLL/COMPASS subunits and the 19S proteasome in regulating CIITA pIV and MHC class II gene expression and promoter methylation. · Koues OI, Mehta NT, Truax AD, Dudley RK, Brooks JK, Greer SF · Epigenetics Chromatin 2010
PMID 20181089 DOI
What this evidence cannot show
No leukaemia and no KMT2A rearrangement anywhere in this paper; the system is cytokine-inducible MHC-II in mammalian cell lines, and the paper's subject is proteasomal control of transcription initiation. Crucially the attribution is to COMMON MLL/COMPASS subunits - shared across all six H3K4 methyltransferase complexes - not to KMT2A, so this cannot be read as a KMT2A result (see `concept-kmt2-family-attribution-problem`). Fifteen years old, and this beat found no follow-up linking it to menin or to leukaemia. Read: abstract only; record and identifiers fetched 2026-09-20.
Evidence that argues against this (1)
- If the effect at CIITA belongs to SETD1A/SETD1B rather than to KMT2A/KMT2B, the bleximenib result would have to run through a different route than this paper suggests - and Sparbier's class I data show exactly that division of labour is real, with SETD1A/B maintaining H3K4me3 at most active genes and KMT2A/B specialised to bivalent promoters. A shared-subunit result cannot discriminate. Sparbier CE et al. 2023
E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin inhibition induced class II transactivator and MHC class II expression in KMT2A-rearranged and NPM1-mutated AML in vitro and in vivo, by a route the authors attribute to human endogenous retrovirus induction and consequent interferon-stimulated gene upregulation.
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 41144759 DOI
What this evidence cannot show
Cited here only to record that a second, independent group reports CIITA induction under menin inhibition by a different proposed route. This graph's entry for this paper is `cell-state-interferon-herv-mhc2`; it is not duplicated. AML only, murine and xenograft transplant models, abstract read only.
Evidence that argues against this (1)
- The two proposed routes to CIITA - direct chromatin action at the CIITA locus with menin bound there (PMID 39704147) and HERV-driven interferon acting on the interferon-inducible CIITA pIV promoter (PMID 41144759) - have not been tested against each other. They predict different combination partners and different failure modes, and both papers are consistent with either. Hogeling SM et al. 2025
E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In Zhou's published 9,292-locus menin and H2AK119ub target set from KMT2A-rearranged AML, CIITA falls in the H2AK119ub-SOLO group (chr16:10877200) - polycomb-marked and menin-UNBOUND - not in the menin-solo or the menin/H2AK119ub-shared group; NLRC5, the class I counterpart transactivator, falls in the MENIN-SOLO group (chr16:56989555) in the same table.
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 39158067 DOI
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. This row is the join's readout of Zhou's supplementary Table 4 and not a claim the Zhou paper makes in its text about CIITA, which it never discusses.
Evidence that argues against this (1)
- PMID 39704147 reports the opposite for the same locus by a targeted method: ChIP-qPCR confirmed menin binding at the CIITA and HLA-DR loci in AML cells, and HLA-DR induction by JNJ-75276617 was lost in CIITA-null MV4-11. The two are not straightforwardly reconcilable, and neither is obviously wrong - a genome-wide called set with a threshold can miss a real but modest peak, while a targeted ChIP-qPCR at a chosen amplicon can report occupancy a genome-wide caller would not credit. The cells also differ (OCI-AML2/KMT2A::AFDN-dominated set versus MV4-11/KMT2A::AFF1). This entry records the disagreement rather than resolving it. Hogeling SM et al. 2025
E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CIITA is a nucleocytoplasmic shuttling protein whose subcellular distribution is a balance, not a state: a classical SV40-like nuclear localisation signal at residues 405-414 is required for nuclear localisation and for transactivation - deleting it moves CIITA to the cytoplasm and abolishes activity, and substituting the SV40 NLS rescues both - while leptomycin B blocks the nuclear-to-cytoplasmic movement, showing CRM1-dependent export operates in parallel.
Mechanisms of nuclear import and export that control the subcellular localization of class II transactivator. · Cressman DE, O'Connor WJ, Greer SF, Zhu XS, Ting JP · J Immunol 2001
PMID 11564775 DOI
What this evidence cannot show
Deletion and transplantation experiments on transfected constructs, so the mapping is of sufficiency and necessity for an overexpressed protein rather than of the endogenous steady state. Not a haematopoietic malignancy system. The leptomycin result identifies CRM1-dependence, which connects CIITA to this graph's XPO1/CRM1 export axis but was not measured there.
Evidence that argues against this (1)
- An earlier and partly conflicting model from the same field attributes CIITA nuclear import to GTP BINDING by its nucleotide-binding domain rather than to a classical NLS, and the same group subsequently reassigned that domain's role from import to EXPORT. The literature therefore contains two mechanisms for getting CIITA into the nucleus published four years apart, with the second paper revising the first, so a single-signal account of CIITA localisation is not settled. Harton JA et al. 1999

Connected to

← related toThe menin/Polycomb split between NLRC5 and CIITA does not extend to their pathways, and the MHC locus is structurally invisible to the method that found it
THE POLYCOMB-MARKED HALF: menin-unbound, consistent with the published indirect route.
regulates →HLA-DRA - the non-polymorphic alpha chain, and the only HLA-DR chain any source on this beat names explicitly
class II transactivator; CIITA knockout abolishes menin-inhibitor-induced HLA-DR in MV4-11
regulates →HLA-DRB1 - the polymorphic beta chain, one of several that can make an HLA-DR dimer, and the reason a chain cannot be inferred from a flow result
class II transactivator acting at the MHC-II promoter SXY module
regulates →HLA-DR - a two-chain MHC class II heterodimer, so no single gene symbol denotes the surface marker a flow report calls HLA-DR
the transactivator behind the HLA-DR surface marker a flow report reads
← bindsMEN1 / menin — the adaptor the fusion cannot work without
menin occupancy at the CIITA and HLA-DR loci confirmed by ChIP-qPCR; contrast with no menin at bivalent class I promoters
← regulatesBleximenib (JNJ-75276617) — menin inhibitor with a cleaner cardiac profile, and the only one with a 2-year-old floor
raises CIITA mRNA; HLA-DR induction lost in CIITA-null MV4-11
part of →The interferon state is not baseline in this disease — it is something a menin inhibitor creates, through endogenous retrovirus induction and MHC class II
the transactivator the HERV-interferon route converges on
← related toThe class I and class II arms of menin inhibition are different mechanisms - the class I effect was tested against viral mimicry and NF-kB and excluded both
the class II arm, which does have a transactivator knockout proof
supports →Menin inhibition restores graft-versus-leukaemia only where MHC class II is limiting - so the post-transplant maintenance rationale may hold in myeloid disease and fail in B-precursor infant ALL
CIITA-null MV4-11 has lower baseline HLA-DR and no drug response - baseline CIITA level sets the achievable induction
← related toNLRC5 - the MHC class I transactivator, and the route by which interferon activates class I when KMT2A and KMT2B are both gone
Zhou's locus set splits them: NLRC5 menin-solo, CIITA H2AK119ub-solo - the class I and class II transactivators regulated oppositely
← related toBounded unreachable: the Blood supplemental table that three entries read their NLRC5 and CIITA group assignments from cannot be retrieved by ANY programmatic route - PMC serves a landing page and the publisher 403s this client - so those claims are re-readable but not re-verifiable without a human's institutional access
its H2AK119ub-solo assignment at chr16:10877200 rests on the unreachable supplemental Table 4
← related toU-937 (CVCL_0007) - the single line carrying this graph's menin-independence argument, and it is adult, monocytic, historically contaminated, and exists as two variants nobody here distinguishes
CIITA TURNS UP AS A P-TEFb-ASSOCIATED VARIABLE HERE, interacting with cyclin T1 and recruited to nuclear bodies by TRIM22, and it is one of the two markers separating the U-937 variants. The immune thread and the P-TEFb thread meet inside the comparator line.
← related toThe MHC was never invisible - the resolver was wrong - and once the classical chains are joined the class I machinery is bivalent, not unmarked
ALSO UNCHANGED: CIITA remains H2AK119ub-only, and the class II set stays flat even with B2M restored.
supports →A partner's 'normal' compartment is usually read off a different tissue, and for at least two KMT2A partners that reading is wrong in blood cells
CIITA is nucleocytoplasmic by design; calling it a nuclear transcription factor drops the regulated half of its biology
related to →Two pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine
CIITA nuclear export is leptomycin-B-sensitive and therefore CRM1/XPO1-dependent, connecting the MHC class II axis to this graph's export axis
← depends onMenin inhibition restores graft-versus-leukaemia only where MHC class II is limiting - so the post-transplant maintenance rationale may hold in myeloid disease and fail in B-precursor infant ALL
the transactivator step where this hypothesis predicts the lineage restriction sits
← testsDoes menin inhibition have any MHC class II headroom to work with in B-precursor infant ALL? A flow cytometry experiment on samples that already exist
CIITA transcript is a primary readout alongside surface HLA-DR/DP/DQ
← related toHalf the PRC1.1 intersection was free all along: Zhou's locus set is a publisher supplementary table, and 159 of this graph's gene entries are in it
CONSTRAINS THE MHC-II ROUTE: CIITA is H2AK119ub-marked and menin-unbound in this dataset, so a menin-inhibitor effect on class II cannot be direct menin loss at CIITA.