XPO1 / exportin-1 (CRM1) - the cell's main nuclear export receptor, and a chromatin-bound transcriptional scaffold

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• XPO1 is common-essential at a DepMap mean of -2.14 across 1,208 lines. There is no therapeutic index available from the target's biology; any window has to come from schedule and from the tumour's greater reliance, not from selectivity.
• XPO1 exports many tumour suppressors as well as oncogenic cargo, so inhibition is simultaneously pro- and anti-leukaemic in ways that are cargo-specific and not predictable from the target.
• If the chromatin-bound pool is the therapeutically relevant one, every existing XPO1 inhibitor engages it only incidentally - they were designed and optimised against the export function, and no assay in clinical use reads out chromatin occupancy.
• ESSENTIAL-FUNCTION TOXICITY — XPO1 is pan-essential with a Chronos mean of -2.142 across 1,208 lines and is depleted in 99 percent of them, so there is no therapeutic window from selectivity - the window has to come from dose and schedule. The erythroid finding adds a specific, testable on-target effect in a second haematopoietic lineage, and in an infant already anaemic from marrow replacement the direction of that effect is not obvious a priori.
• Pairing an XPO1 inhibitor with an epigenetic agent is currently justified by synergy screens in unrelated malignancies and by no mark measurement anywhere. That is exactly the configuration in which a combination advances on a plausible story and fails for a reason nobody looked for: if XPO1's chromatin pool is a general co-activator position, the synergy is additive requirement rather than mechanistic cooperation, and the combination will carry both drugs' toxicities - including the erythroid-progenitor cost this entry already records - without the supra-additive benefit the rationale promises.

1. What puts XPO1 on chromatin in the first place? Every paper in this literature starts from the fact that it is already there, and nothing identifies the tether, the sequence feature or the modification that recruits it.
2. Is the chromatin-bound pool a distinct biochemical species - a different conformation, a different post-translational state, cargo-free versus cargo-loaded - or just the same molecules in transient contact? Nobody has separated the two pools biochemically.
3. Does a SINE compound acting at Cys528 in the NES groove affect chromatin-bound XPO1 through the same chemistry as it affects export, or does it work here by degrading XPO1 and its docked partners? The published KPT-330 experiments confound the two.
4. The MEIS1 locus is named alongside HOX in the 2026 perspective but this graph has no XPO1 occupancy data at MEIS1 in any KMT2A-rearranged system. Is MEIS1 a second shared address?
5. Does XPO1 inhibition alone, without a menin inhibitor, move any differentiation marker in a KMT2A-rearranged cell? Every cell-state readout on record is from the combination, and the single-agent arm is the cheapest missing experiment in this entry.
6. Selinexor enhances terminal erythroid maturation in thalassaemic progenitors and is credited with promoting monocytic differentiation in AML. Are these one mechanism read in two lineages, or two? Measuring nuclear HSP70 and GATA1 in a KMT2A-rearranged blast under selinexor would separate them.
7. Is chromatin-bound XPO1 in a leukaemia cell locus-restricted to HOX, or is it the same broad p300-co-occupied pool reported in PMID 38917791? One XPO1 CUT&RUN with a p300 track in the same cells answers it, and no published experiment distinguishes the two.
8. Is chromatin-bound XPO1 a general property of active chromatin or a leukaemia-specific address? The p300 co-occupancy result (PMID 38917791) makes the general reading live, and the discriminating experiment is an XPO1 ChIP in a KMT2A-rearranged cell compared against a non-leukaemic line of the same lineage - not against a different disease.
9. Does XPO1 inhibition move any histone mark at KMT2A-fusion target loci? This graph records ziftomenib/selinexor synergy in KMT2A-rearranged AML and a chromatin-bound XPO1 pool at HOX and MEIS1, and it has no chromatin pharmacodynamic endpoint for that combination. The designed experiment exists; only the KMT2A-rearranged arm is missing from it.
10. Is the repeated A485/XPO1-inhibitor synergy - now reported in multiple myeloma and in DLBCL - a shared mechanism at chromatin or just two independently required genes? The discriminating measurement is histone acetylation at XPO1-occupied regulatory elements under each agent alone and in combination, and it has not been made in any of the three reports.
11. If chromatin-bound XPO1 is a general co-activator position rather than a specific address, does it have a MARK signature? XPO1 occupancy is reported at 'active regulatory regions', which is a category defined by marks nobody has measured alongside XPO1 in the same cells. Co-profiling XPO1 with H3K27ac and H3K4me1 would say whether the pool tracks enhancers, promoters or neither, and would settle this entry's own specificity correction.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   XPO1 mediates nuclear export of cargoes bearing a leucine-rich NES, binding cooperatively to the NES and to RAN-GTP in the nucleus with RANBP3, docking at the nuclear pore through nucleoporin contacts, and releasing cargo in the cytoplasm when RANBP1 and RANGAP1 drive Ran-GTP hydrolysis; the reviewed human record is O14980, primary gene name XPO1, 1,071 aa, with HEAT repeats annotated from residue 217 to 1,039 and a Ran-interaction region at 327-450.

   UniProtKB - O14980 (XPO1_HUMAN), Exportin-1 · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   Database record fetched live on 2026-09-20 via the UniProt REST API with gene_primary and length requested, per brief rules 62-65. The FUNCTION text is a curated synthesis of several primary papers (the record cites PMIDs 9311922, 9323133, 15574332, 20921223), not a single measurement. Residues 528 (Cys) and 571 (Glu) were read directly off the fetched sequence rather than from recall.

   ▸Evidence that argues against this (1)

   • PUBLISHED CONFLICTING RESULT against the completeness of the reviewed record. UniProt's FUNCTION and subcellular-location text for O14980 carries no chromatin term, but Chen et al. demonstrate that XPO1 directly binds chromatin, co-occupies hundreds of loci with p300, and that degrading XPO1 diminishes p300 chromatin occupancy and phenocopies p300 inhibition. The curated record is not wrong; it is incomplete in exactly the direction this beat depends on, and an entry whose load-bearing first evidence item is the reference annotation will systematically understate the chromatin pool. Chen YF et al. 2024
2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

   XPO1/CRM1 is detectable on chromatin at active regulatory regions including the HOX clusters and the MEIS1 locus, and a 'pre-bound XPO1 platform' model holds that nucleoporin (NUP98/NUP214) fusions and mutant NPM1 are recruited to these loci through FG-repeat-XPO1 or NES-XPO1 interactions coupled with partner-encoded chromatin contacts, potentially lowering the threshold for LLPS-linked condensate formation.

   Beyond nuclear export: chromatin-bound XPO1/CRM1 as a transcriptional scaffold. · Oka M · International Journal of Hematology 2026
   PMID 42565971DOI
   ▸What this evidence cannot show

   A PERSPECTIVE/REVIEW by the author of the primary chromatin-bound CRM1 papers, so it is a map of his own position rather than independent corroboration. Cited here for the framing and for the MEIS1 locus, which this graph had not recorded; every underlying measurement is cited to its own primary source elsewhere in this beat. The LLPS-threshold claim is a proposal, not a measurement, and this graph's standing caveat on phase-separation assays applies. Abstract-level reading only.

   ▸Evidence that argues against this (1)

   • PUBLISHED CONFLICTING RESULT, and it is the strongest available objection to the 'pre-bound XPO1 platform' model as an ADDRESS. Measured by an independent group with an independent chemical tool, chromatin-bound XPO1 is not locus-restricted: XPO1 and p300 co-occupy HUNDREDS of chromatin loci, and degrading XPO1 with C646 or S109 reduces the chromatin occupancy of both, which is why an XPO1 degrader phenocopies a p300 inhibitor. A factor sitting at hundreds of p300-marked active loci is a general chromatin cofactor, not a postal address that distinguishes one set of lesions from another. Finding XPO1 at HOXA in a HOX-driven leukaemia line is then the expected observation, and the specificity has to come from the lesion's own chromatin contacts rather than from XPO1. Chen YF et al. 2024
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In the human T-ALL line LOUCY, ChIP-seq shows CRM1 selectively bound at HOXA and especially HOXB cluster regions; knocking down SET-Nup214 down-regulates HOX genes without significantly reducing chromatin-bound CRM1, indicating CRM1 is the recruiter rather than the cargo; and the same chromatin-bound CRM1 recruits NPM1c via its NES.

   Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. · Oka M, Mura S, Otani M, et al. · eLife 2019
   PMID 31755865DOI
   ▸What this evidence cannot show

   Human leukaemia CELL LINES only (LOUCY, MEGAL, with K562/HL60/HEL as comparators); no patient sample and nothing in infant B-lineage KMT2A::AFF1. The recruiter conclusion rests on a knockdown, which leaves residual protein. Recorded in full in `mechanism-set-nup214-crm1-is-the-address-not-the-fusion`; cited here only for the chromatin-bound pool's existence and ordering.

   ▸Evidence that argues against this (1)

   • The same paper reports KPT-330-sensitive CRM1 signals at HOX regions in HEL cells, which do NOT carry SET-Nup214, and states the biological significance is undetermined. Chromatin-bound XPO1 at HOX is therefore not by itself a fusion-specific event. Oka M et al. 2019
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Recurrent XPO1 hot-spot mutations, predominantly E571K or E571G, disrupt conserved biophysical interactions in the NES-binding groove and confer novel cargo-binding abilities; crystal structures of wild-type and E571K XPO1 bound to KPT-185, selinexor (KPT-330) and eltanexor (KPT-8602) are highly similar, indicating SINE activity is not affected by E571 mutations.

   Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia. · Walker JS, Hing ZA, Harrington B, et al. · Journal of Hematology & Oncology 2021
   PMID 33451349DOI
   ▸What this evidence cannot show

   CLL, not the leukaemia this graph is about, and abstract-level for this beat. Cited here for the structural localisation of the drug-binding cysteine and the hot-spot residue; the disease claims are held in `mechanism-xpo1-e571k-hotspot-change-of-function`. The SINE-binding structures argue that E571 mutation does not cause SINE resistance and say nothing about acquired C528S.

   ▸Evidence that argues against this (1)

   • PUBLISHED CONFLICTING RESULT on the conclusion drawn from the structures. The structures show that E571 mutation does not alter SINE binding; they say nothing about whether SINE resistance is achievable, and it demonstrably is - at the residue two helices away. Neggers et al. engineered C528S into multiple leukaemia cell lines with CRISPR/Cas9 and found that a single HETEROZYGOUS substitution confers resistance to selinexor as effectively as a homozygous one, i.e. the resistance is dominant and one allele of one codon is sufficient. 'SINE activity is not affected by E571 mutations' is true and is routinely read as 'the SINE class has no target-site resistance liability', which this paper refutes. Neggers JE et al. 2016
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset

   In a genome-wide DepMap scan over 17,728 protein-coding genes comparing 11 Cellosaurus-annotated KMT2A-rearranged leukaemia lines with 43 other leukaemia lines, XPO1 has a mean gene effect of -2.332 in the rearranged arm and -2.263 in the comparator, a difference of only -0.070, ranking 2,228 of 17,728; its pan-essentiality across 1,208 lines is -2.142.

   DepMap KMT2A-selective dependency scan (full genome), analyses/depmap-kmt2a-selective-scan-full · Oncofusion Knowledge Graph project · internal analysis over DepMap CRISPR gene effect 2026
   ▸What this evidence cannot show

   This graph's own scan, generated 2026-09-19, read directly from analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-20. Standing DepMap caveats apply and one bites hard: XPO1 sits at a pan-essentiality of -2.14, deep in the FLOOR-COMPRESSION regime the brief names, where almost no dynamic range remains for selectivity to appear. So the near-zero difference is UNINTERPRETABLE rather than a demonstrated absence of selectivity. The 11 KMT2A-rearranged lines are myeloid-enriched and none is infant-derived, and the DepMap release version is not stated by the API.

   ▸Evidence that argues against this (1)

   • AUTHORS' OWN STATED LIMITATION of the instrument that produced -2.332 and -2.142. The Chronos authors open by stating that CRISPR loss-of-function screens 'exhibit a number of biases and artifacts that can confound the results', and Chronos is explicitly an inference of fitness effects from an explicit model of CELL PROLIFERATION DYNAMICS after knockout. A gene effect of -2.3 is therefore a statement about how fast a population stops expanding over the screen, not about how much XPO1 activity a cell requires, and it carries no information at all about differentiation, quiescence or drug-conditional phenotypes. The floor-compression caveat in this item is correct; the deeper point is that the quantity being compressed is proliferation rate. Dempster JM et al. 2021
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.preprint

   In KMT2A-rearranged and NPM1-mutant AML, the menin inhibitor ziftomenib combined with the XPO1 inhibitor selinexor synergistically inhibited growth of multiple cell lines, suppressed colony formation of primary CD34-positive KMT2A-rearranged progenitor cells without affecting normal stem cells, downregulated HOXA9 and MEIS1 while upregulating the monocytic differentiation marker CD11b, and improved survival in MV4;11, OCI-AML3 and patient-derived xenograft models; mechanistically XPO1 stabilises menin's binding to chromatin and its interactions with KMT2A and KMT2A/MLLT3.

   Combined Menin and XPO1 inhibition drive synergistic antileukemic activity in KMT2Ar and NPM1-m AML. · Uddin MH, Dhiman S, Han Y, Aboukameel A, Dhillon V, Aguillar J, Buck S, Deol A, Boerner JL, Polin L, Kessler L, Burrows F, Yang J, Azmi AS, Maciejewski JP, Cutler J, Du Y, Balasubramanian SK · bioRxiv 2026
   PMID 41959134DOI
   ▸What this evidence cannot show

   A bioRxiv PREPRINT, not peer reviewed, and the graph should not upgrade this until it is. AML only - MV4;11 is KMT2A::MLLT3 and OCI-AML3 is NPM1-mutant; there is no B-lineage and no KMT2A::AFF1 arm. Every cell-state readout, including the CD11b differentiation marker, is reported for the drug COMBINATION, so the XPO1-alone contribution to the state change is not measured. Read: abstract only.

   ▸Evidence that argues against this (1)

   • A CRISPR viability screen finds no KMT2A-selective requirement for XPO1 at all. In this project's own genome-scale scan XPO1 is -2.332 in the 11 KMT2A-rearranged lines against -2.263 in 43 other leukaemia lines, a difference of -0.070 at rank 2,228 of 17,728, on a gene whose pan-line Chronos mean is -2.142. That is floor compression: with almost no dynamic range left, the difference is uninterpretable rather than small, and it means 'XPO1 is required in KMT2A-rearranged cells' is a statement about all cells. Oncofusion knowledge graph, analyses/depmap-kmt2a-selective-scan-full; DepMap Chronos via Open Targets; 11 KMT2A-rearranged versus 43 other leukaemia lines, 17,728 genes 2026
7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Inhibiting XPO1 in a non-leukaemic haematopoietic cell type produces the opposite kind of effect: in erythroid progenitors from patients with severe beta-0-thalassaemia/HbE, selinexor was the most effective of nine XPO1 inhibitors at ENHANCING terminal erythroid maturation, associated with nuclear retention of HSP70, stabilisation of GATA1 and a dose-dependent increase in cytoplasmic HSP70.

   Inhibition of XPO1 by selinexor enhances terminal erythroid maturation through modulation of HSP70 trafficking in severe β0-thalassemia/HbE. · Khamphikham P, Tantiworawit A, Anuchapreeda S · PLoS One 2025
   PMID 40997022DOI
   ▸What this evidence cannot show

   Primary erythroid progenitors from nine patients with a haemoglobinopathy, not from healthy donors and not from leukaemia. The cell type is a cultured erythroid progenitor undergoing terminal maturation and the graph has no node for it. This establishes a lineage-specific consequence of XPO1 inhibition; it says nothing about XPO1 in a KMT2A-rearranged blast. Read: abstract only.

   ▸Evidence that argues against this (1)

   • The same drug class in the AML setting is credited with pushing blasts toward monocytic differentiation, so 'selinexor promotes maturation' is being asserted in two lineages with two different mechanisms and, in the AML case, only as part of a combination. A shared word - maturation - across an erythroid HSP70/GATA1 mechanism and a myeloid HOXA9/MEIS1 mechanism is not shared biology. Uddin MH et al. 2026
8. E_q72_xpo1_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   NONE OF XPO1'S FOUR UNIPROT LOCATIONS CARRIES ANY EVIDENCE CODE. Fetched from UniProtKB 2026-09-21, O14980 (XPO1_HUMAN, primary gene XPO1, 1,071 aa) lists 'Cytoplasm', 'Nucleus, nucleoplasm', 'Nucleus, Cajal body' and 'Nucleus, nucleolus', and the SUBCELLULAR LOCATION comment carries a free-text note - 'Located in the nucleoplasm, Cajal bodies and nucleoli. Shuttles between the nucleus/nucleolus and the cytoplasm'. EVERY ONE OF THOSE FIVE STRINGS IS UNCODED: no ECO:0000269, no ECO:0000305, no ECO:0000250, nothing. XPO1 sits in the 10.7% of this graph's accession-carrying gene entries whose UniProt locations have no evidence code at all.

   UniProtKB entry O14980 (XPO1_HUMAN), SUBCELLULAR LOCATION comment read with evidence codes · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   A database state on a date, and an UNCODED annotation IS NOT A WRONG ANNOTATION - XPO1 shuttling is among the best-established facts in cell biology, and the absence of a code here reflects curation history for a long-standing entry, not doubt. What it does mean is narrow and worth carrying: this entry's existing data.subcellular_location_uniprot field lists those four strings, and a reader is entitled to assume a UniProt location is attributed. It is not. Anyone building on the Cajal-body or nucleolar value in particular should find and cite the primary observation, because the database will not hand it to them. See ana-uniprot-localization-is-not-a-measurement-in-a-quarter-of-this-graph.

   ▸Evidence that argues against this (1)

   • The compartment that matters for this graph is not in that list at all. XPO1's leukaemia-relevant pool is CHROMATIN-BOUND, and chromatin is not among UniProt's four values - so the database is simultaneously unattributed on what it does say and silent on the thing the export-axis hypothesis rests on. localization-xpo1-chromatin-bound-versus-soluble-pool records that the two pools have never been separated as biochemical species. Oka M et al. 2019
9. E_q72_xpo1_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   CHROMATIN-BOUND XPO1 MAY BE A GENERAL CO-ACTIVATOR POSITION RATHER THAN A LEUKAEMIA-SPECIFIC ADDRESS, AND THIS GRAPH SHOULD NOT QUIETLY STRENGTHEN THE OPPOSITE. In a non-leukaemic chemical-genetics study, the compound C646 - long used as a p300 inhibitor - was shown to DEGRADE XPO1, with its cellular phenotypes abrogated in cells carrying the XPO1 C528S drug-resistance allele; and P300 AND XPO1 CO-OCCUPY HUNDREDS OF CHROMATIN LOCI, with degradation of XPO1 by C646 or by the modulator S109 diminishing the chromatin occupancy of BOTH. Direct XPO1 degradation phenocopies p300 inhibition.

   C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function. · Chen YF, Rahman A, Sax JL, Atala Pleshinger MJ, Friedrich RM, Adams DJ · Cell Chem Biol 2024
   PMID 38917791DOI
   ▸What this evidence cannot show

   Abstract read in full; full text not read. NOT A LEUKAEMIA SYSTEM and no KMT2A fusion anywhere in it (brief rule 73). Already cited 7 times in this graph, including in this entry's own E1/E2 and in ana-xpo1-chromatin-measurements-never-made and hyp-xpo1-is-a-shared-address-for-hoxa-driven-leukaemia - rule 82 applies and this item is recorded as a LOCALISATION caveat, not as a new finding. THE POINT IS DEFLATIONARY: a chromatin-bound XPO1 that co-occupies hundreds of loci with p300 is compatible with XPO1 being a general component of active chromatin, in which case the HOX-cluster occupancy reported in leukaemia lines is an instance of a general property rather than a fusion-specific address. The co-occupancy is a crosslinked-ChIP result and reports proximity, not residence, and losing both signals after degrading one protein does not establish that one recruits the other.

   ▸Evidence that argues against this (1)

   • The directional experiment in leukaemia points the other way and is the strongest argument that the chromatin pool is not merely decorative: in the human T-ALL line LOUCY, ChIP-seq with two independent anti-CRM1 antibodies finds CRM1 selectively at HOXA and especially HOXB cluster regions, and knocking down SET-Nup214 down-regulates HOX genes WITHOUT significantly reducing chromatin-bound CRM1 - i.e. CRM1 is upstream, the recruiter rather than the cargo. That is a specific, locus-restricted, order-of-assembly result. It is also in a SET::NUP214 T-ALL line, not a KMT2A-rearranged cell, and no XPO1 ChIP has ever been done in a KMT2A-rearranged system. Oka M et al. 2019
10. E8weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    THE XPO1-EPIGENETICS INTERSECTION IS COMBINATION PHARMACOLOGY, NOT MECHANISM: the p300/CBP histone acetyltransferase inhibitor A485 and the XPO1 inhibitor KPT-8602 show synergistic antitumour activity in multiple myeloma.

    Synergistic Antitumor Activity of HAT Inhibitor A485 and XPO1 Inhibitor KPT8602 in Multiple Myeloma. · Xu H, Wu W, Jiang Y, et al. · Cancer Med 2026
    PMID 42231094DOI
    ▸What this evidence cannot show

    Abstract-level read; full text not read in this tranche. MULTIPLE MYELOMA - a mature plasma-cell malignancy, not leukaemia, not KMT2A-rearranged and not paediatric, so rule 73 applies and nothing about the index disease follows. Marked WEAK because a synergy result establishes a drug interaction and no mechanism: no histone acetylation or any other mark is reported as a readout in the abstract, so the pairing of an acetyltransferase inhibitor with an export inhibitor is not evidence that XPO1 acts on acetylation. A485 is itself a tool-grade compound with its own selectivity questions. Not cited anywhere in this corpus before 2026-09-21, verified with scripts/check-citation-reuse.py.

    ▸Evidence that argues against this (1)

    • The combination that actually matters for this project is a different one and is already in this entry, which is why the myeloma result is recorded at weak confidence rather than built on. In KMT2A-rearranged and NPM1-mutant AML, the menin inhibitor ziftomenib combined with the XPO1 inhibitor selinexor synergises - the right disease, the right lesion, and a mechanistic rationale through the chromatin-bound XPO1 pool. That combination also has no histone-mark readout, which is the actual gap: the epigenetic case for pairing XPO1 inhibition with anything in this disease rests on synergy screens in every instance, and on a mark measurement in none. Uddin MH et al. 2026
11. E9weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    The same acetyltransferase/export pairing is reported in a second B-lineage-adjacent malignancy: targeting EP300 with A485 in diffuse large B-cell lymphoma is efficacious and shows synergistic effects with XPO1 inhibition.

    Targeting EP300 in diffuse large b-cell lymphoma: efficacy of A485 and synergistic effects with XPO1 inhibition. · Jiang Y, Xing D, He X, et al. · BMC Cancer 2025
    PMID 40437414DOI
    ▸What this evidence cannot show

    Abstract-level read; full text not read. DIFFUSE LARGE B-CELL LYMPHOMA - a mature B-cell malignancy, not precursor B-ALL and not KMT2A-rearranged. Recorded only because it is the second independent report of the A485/XPO1-inhibitor pairing and so raises the pairing above a single-paper observation; like the myeloma result it reports a growth and synergy readout and, at abstract level, no histone acetylation measurement, so it adds replication of a drug interaction and no mechanism. Not cited anywhere in this corpus before 2026-09-21.

    ▸Evidence that argues against this (1)

    • The tempting mechanistic bridge - that chromatin-bound XPO1 cooperates with acetyltransferases at active regulatory elements, which would explain the synergy - is exactly the inference this entry's own correction warns against. Chromatin-bound XPO1 may be a GENERAL CO-ACTIVATOR POSITION rather than a leukaemia-specific or locus-specific address, and this graph explicitly declines to quote the HOXA/MEIS1 occupancy as a specific address. If XPO1 sits at active regulatory regions generally, then synergy with a p300/CBP inhibitor is expected wherever both are required and carries no information about a shared mechanism at any particular locus. Chen YF et al. 2024
12. E10weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    Third instance of the same shape, from the eraser side: nuclear-to-cytoplasmic transport is a druggable dependency in HDAC7-driven small-cell lung cancer, so an XPO1 dependency has been reported downstream of a class IIa histone deacetylase programme.

    Nuclear to Cytoplasmic Transport Is a Druggable Dependency in HDAC7-driven Small Cell Lung Cancer. · Qin T, Wang J, Wang J, et al. · Adv Sci (Weinh) 2025
    PMID 39887933DOI
    ▸What this evidence cannot show

    Abstract-level read; full text not read. SMALL-CELL LUNG CANCER - a neuroendocrine epithelial tumour with no relationship to this disease, and the HDAC7 connection is a driver-programme context rather than a demonstrated XPO1-HDAC7 biochemical relationship. Already cited once in this corpus (gene-hdac7). Recorded here as the third member of a pattern - XPO1 inhibition intersecting acetylation machinery in three unrelated malignancies - and the pattern's honest reading is that XPO1 is broadly required and therefore synergises broadly, not that it has an acetylation mechanism.

    ▸Evidence that argues against this (1)

    • A pattern of synergy across malignancies says nothing about the therapeutic window, and this entry already records the counterexample in the relevant tissue. Inhibiting XPO1 in a non-leukaemic haematopoietic cell type produces the opposite kind of effect in erythroid progenitors, which is the on-target cost that matters in an infant with a marrow disease. Three synergy reports in myeloma, DLBCL and small-cell lung cancer add nothing to that calculus, and none of them is in a haematopoietic progenitor. Khamphikham P et al. 2025

• ← inhibitsSelinexor (XPO1 inhibition) — a real paediatric response rate attached to an unproven mechanism in KMT2A-rearranged disease

  covalent SINE at Cys528 in the NES-binding groove

• binds →NUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions

  XPO1 docks on NUP214 FG repeats at the pore and in the fusion

• recruits →SET::NUP214 (TAF-Ibeta-NUP214, SET-CAN), cryptic del(9)(q34.11q34.13) - a HOXA-driving fusion of a histone chaperone to a nucleoporin, with no KMT2A and no menin-binding motif

  chromatin-bound CRM1 is upstream of the fusion at HOX

• regulates →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  chromatin-bound XPO1 at HOXA/HOXB clusters

• supports →SET::NUP214 has no address of its own: chromatin-bound CRM1 is already at HOX, and the fusion's FG repeats dock onto it

  the receptor behind the borrowed address

• related to →A ten-residue export signal is the 5' partner's whole contribution - and the field disagrees about which direction it pushes

  the receptor the CALM NES is recognised by

• ← depends onDocking onto pre-bound XPO1 is a general route to leukaemic chromatin, used by at least seven different lesions - not three coincidences

  the pre-bound platform is XPO1 itself

• ← depends onA 2026 preprint puts XPO1 upstream of the menin interface itself: XPO1 reported to stabilise menin on chromatin and menin's binding to KMT2A and KMT2A::MLLT3

  the reported stabilising factor

• ← part ofTwo pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine

  which pool of the protein is which

• ← bindsNPM1c and XPO1: one drug, one output, two incompatible mechanisms - is the mutant needed in the cytoplasm or on the chromatin?

  NPM1c C-terminal NES binds XPO1

• ← depends onDEK::NUP214 is the sixth lesion on the XPO1 address - and the only one where the drug response was measured in primary patient cells

  XPO1-dependent chromatin binding at FOXC1 and HOXA/HOXB

• ← bindsUBTF tandem duplications INVENT an export signal, and that invented signal is what puts the protein on chromatin - the cleanest proof the XPO1 address is real

  NES motifs created de novo by the duplication bind XPO1

• ← part ofXPO1 E571K: a change-of-function hot spot in the NES-binding groove - and it does NOT confer resistance to the drugs that bind the same groove

  a recurrent somatic hot spot in the NES-binding groove

• ← related toXPO1 mutation in acute leukaemia, counted with denominators and a positive control: 1 of 739 B-ALL, 0 of 584 paediatric AML, 0 of 1,103 adult AML

  1 of 739 sequenced B-ALL, 0 of 1,687 sequenced AML

• ← inhibitsEltanexor (KPT-8602) - the second-generation SINE whose whole point is that you can give it more often

  covalent second-generation SINE at Cys528, dosed more frequently

• ← depends onChromatin-bound XPO1 as a shared, druggable address for HOXA-driven leukaemia - and the objection that it may be a general chromatin cofactor rather than an address at all

  the platform

• ← related toTwo reasons XPO1 is a hard target: every cell needs it, and blocking it switches on a survival pathway

  DepMap mean gene effect -2.14 across 1,208 lines

• ← related toHow a lift operator became a postal address: the idea behind the XPO1 axis, in plain language

  layman explainer for the protein

• ← regulatesXPO1 mRNA goes UP when you inhibit the protein - the pharmacodynamic marker that made the paediatric trial interpretable, and what it cannot tell you

  XPO1 mRNA rises when XPO1 protein is inhibited

• regulates →The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia

  XPO1 inhibition WITH a menin inhibitor raises CD11b and lowers HOXA9/MEIS1 in KMT2A-rearranged AML; combination evidence only, XPO1-alone contribution unmeasured, and the source is a preprint

• related to →Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here

  ziftomenib plus selinexor suppressed colony formation of primary CD34-positive KMT2A-rearranged progenitors WITHOUT affecting normal stem cells - a sparing claim, not a requirement claim, from a preprint

• ← related toA ten-residue export signal is the 5' partner's whole contribution - and the field disagrees about which direction it pushes

  the NES/clathrin-binding/oligomerisation claims all concern one CALM span and no experiment separates them; the fusion is nuclear in leukaemia cells

• refutes →EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th

  XPO1 and p300 co-occupy HUNDREDS of chromatin loci and an XPO1 degrader phenocopies p300 inhibition (PMID 38917791) - so chromatin-bound XPO1 is a general p300-associated cofactor, not a HOX-restricted postal address, and finding it at HOXA in a HOX-driven line discriminates nothing

• ← refutesXPO1 E571K: a change-of-function hot spot in the NES-binding groove - and it does NOT confer resistance to the drugs that bind the same groove

  the entry's title says the hot spot does not confer resistance to drugs binding the same groove - true of E571 and false of the groove: a single HETEROZYGOUS C528S is sufficient and dominant for SINE resistance (PMID 27634897), so 'XPO1-mutant' is at least two biomarkers pointing opposite ways

• ← refutesXPO1 mRNA goes UP when you inhibit the protein - the pharmacodynamic marker that made the paediatric trial interpretable, and what it cannot tell you

  XPO1 protein is degraded by C646, a compound universally annotated to p300, via a neddylation-dependent molecular-glue mechanism (PMID 38917791) - so XPO1 levels and the feedback that follows them move under agents nobody attributes to XPO1, and the SELHEM children received fludarabine and cytarabine alongside selinexor with no comparator arm

• related to →Two pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine

  the two XPO1 pools; UniProt annotates neither with an evidence code and omits chromatin

• supports →Three measurements the export axis needs and nobody has published: XPO1 occupancy in KMT2A-r, H3K79 under an XPO1 inhibitor, and CRM1 occupancy under a menin inhibitor

  no XPO1 localisation measurement of any kind exists in a KMT2A-rearranged cell

• related to →Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout

  the locus-restricted chromatin CRM1 signal is a SET::NUP214 T-ALL result, not a KMT2A one

• refutes →Chromatin-bound XPO1 as a shared, druggable address for HOXA-driven leukaemia - and the objection that it may be a general chromatin cofactor rather than an address at all

  XPO1 and p300 co-occupy hundreds of loci, so chromatin-bound XPO1 may be a general cofactor position

• ← related toSMARCB1 (BAF47/INI1/SNF5) - zero entries, zero mentions and, on the evidence, correctly so: it is lost in primary AML rather than required

  SMARCB1 has no bona fide NLS but a MASKED NES; C-terminal truncation unmasks it, exportin-1 exports the protein, and selinexor puts it back in the nucleus and kills rhabdoid cells (PMID 34003336) (Q91 2026-09-22)

• ← related toNUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions

  DEK::NUP214 chromatin occupancy at FOXC1 and HOXA/HOXB by CUT&RUN is XPO1-DEPENDENT and is lost on XPO1 inhibition, alongside selective selinexor/eltanexor sensitivity in t(6;9) AML (PMID 40204893) (Q91 2026-09-22)

• tests →Export or docking? A locus-resolved H3K79me2 ChIP under an XPO1 inhibitor separates the two CALM-AF10 models, and it has never been run

  THE DESIGNED-AND-UNRUN EXPERIMENT THAT WOULD SUPPLY THIS ENTRY'S EPIGENETIC CONTENT: spike-in-normalised locus-resolved H3K79me2 under selinexor, which in CALM-AF10 discriminates the export from the docking model (opposite predictions for the focal HOXA peak) and in a KMT2A-rearranged line would answer whether blocking export moves a mark at all.

• related to →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  POSITION, NOT A MARK: chromatin-bound XPO1 is detectable at active regulatory regions including the HOX clusters and the MEIS1 locus. Qualified by this entry's own 2026-09-21 correction that the pool may be a general co-activator position rather than a specific address; no mark has been co-profiled with it.

• related to →Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here

  WRITES, ERASES AND READS NOTHING: a karyopherin-beta HEAT-repeat superhelix with Cys528 in the NES groove and no chromatin module. The only published XPO1-epigenetics intersection is combination synergy with acetylation-machinery agents in three unrelated malignancies, with no histone-mark readout in any of them.