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Mechanismstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q61-export-axis

XPO1 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

also called XPO1 E571K · XPO1 E571G · exportin-1 hotspot mutation

One spot in XPO1 is mutated over and over in a few B-cell cancers. It sits in the pocket that grips cargo, and it changes which cargo gets gripped rather than switching the protein off. Reassuringly, the drugs that bind that same pocket still work on the mutant.

The same thing, for a scientist

**Where it came from.** XPO1 was named as one of four recurrently mutated genes in the first whole-genome study of chronic lymphocytic leukaemia, alongside NOTCH1, MYD88 and KLHL6, with XPO1 and NOTCH1 mutations concentrated in the unmutated-IGHV subgroup [E1]. **What the mutation does.** Recurrent XPO1 hot-spot mutations - **predominantly E571K, with E571G** - disrupt highly conserved biophysical interactions in the **NES-binding groove**, conferring **novel cargo-binding abilities** and forcing mis-localisation of critical regulators [E2]. In a 1,286-case multi-centre CLL series, non-synonymous XPO1 mutations (n = 72, predominantly E571K/E571G) associated with high-risk genetic and epigenetic features and accelerated progression; in Eu-XPO1 x Eu-TCL1 mice, B-cell expression of E571K or E571G **accelerated leukaemogenesis** relative to Eu-TCL1 alone [E2]. So it behaves as a **change-of-function accelerant**, not a loss-of-function and not a classical driver on its own. **The drug question, answered structurally.** Crystal structures of **wild-type and E571K XPO1 bound to KPT-185, selinexor (KPT-330) and eltanexor (KPT-8602) are highly similar**, so the authors conclude SINE activity will not be affected by E571 mutations [E2]. An independent group found the opposite of resistance in cells: **XPO1 mutation renders PMBL and classical Hodgkin lymphoma lines MORE sensitive to selinexor**, because mutant XPO1 is degraded faster than wild type [E3]. **Residue check.** Position 571 of O14980 is **E** in the fetched sequence, and position 528 - the SINE cysteine - is **C**. Both verified live on 2026-09-20; neither was taken from recall. The two residues are 43 apart, both in the groove, and confusing them would invert the drug argument. **Does it appear in KMT2A-rearranged leukaemia?** Essentially not - see `ana-xpo1-e571k-across-leukaemia-cohorts` for the counted answer with denominators and a positive control.

Go deeper
The disease distribution, and why it stops at the B-cell border

The E571 hot spot is concentrated in CLL, primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma 13, with scattered reports in adult T-cell leukaemia/lymphoma with CNS involvement 4. It is also a cell-free-DNA-detectable marker in DLBCL, where digital PCR assays for XPO1 E571K, EZH2 Y641N and MYD88 L265P were developed together 5.

What that list has in common is mature B-cell (and one mature T-cell) malignancy. It does not include acute leukaemia of any lineage. A mutation that alters which NES cargoes get exported plausibly matters in a cell whose oncogenic programme runs through NF-kB and JAK/STAT shuttling, and matters less in a cell whose programme is a chromatin lesion. That is a hypothesis, not a finding, and the counted cohort data is the part that is evidence.

Why a non-resistance mutation is worth an entry

Three uses, none of them about CLL:

  1. It proves the groove is mutable without being lethal. A recurrent somatic change at E571 in a common-essential protein tells you the NES groove tolerates substitution, which is a prior for whether acquired resistance at C528 is plausible under SINE pressure. C528S is the canonical laboratory resistance mutation for leptomycin B and the SINEs; the E571 data say nothing about it and it has not been reported clinically in the sources read here.
  2. It is the cleanest available biomarker case, and it points the wrong way for a resistance story. Mutant XPO1 is more selinexor-sensitive in PMBL/cHL, by faster degradation 3. If that generalises, XPO1 mutation is an enrichment biomarker, not an exclusion one.
  3. It supplies the contrast for this beat's main claim. In CLL the mutation is the lesion. In KMT2A-free HOXA leukaemia, wild-type XPO1 is the lesion's accomplice. Two completely different ways for one gene to be involved in cancer, and only one of them produces a genotype you can select patients on.
Facts and figures
mechanism classsomatic variant / change of function
genegene-xpo1
uniprotO14980
length AA1071
residue571
wild type residueE (verified live against the O14980 sequence, 2026-09-20)
location in proteinNES-binding groove; 43 residues from Cys528, the SINE covalent target
functional classchange of function - novel cargo binding and forced mis-localisation, not loss of function
sine resistanceNO - crystal structures of wild-type and E571K bound to KPT-185, selinexor and eltanexor are highly similar; and mutant XPO1 lines are MORE selinexor-sensitive by faster degradation
in kmt2a rearrangedsee ana-xpo1-e571k-across-leukaemia-cohorts - counted, with denominators and a positive control
distinct resistance residueCys528; C528S is the canonical laboratory SINE/leptomycin resistance substitution and is a different residue from the disease hot spot
substitutions reported
[
  "E571K",
  "E571G",
  "E571Q",
  "E571V"
]
diseases
[
  "chronic lymphocytic leukaemia (IGHV-unmutated)",
  "primary mediastinal B-cell lymphoma",
  "classical Hodgkin lymphoma",
  "diffuse large B-cell lymphoma (cfDNA)",
  "adult T-cell leukaemia/lymphoma with CNS involvement (title-level)"
]
How this could bite us back
  • This hot spot is not a vulnerability in this graph's disease. Importing 'XPO1 is mutated in leukaemia' from the CLL literature into a KMT2A-rearranged argument would be a category error - the CLL lesion is the mutation, the KMT2A-free HOXA lesion uses wild-type protein.
  • The absence of an acquired C528S report is an absence of looking as much as an absence of the event; SINE-treated patients are not routinely resequenced at XPO1.
  • If XPO1 mutation status becomes a selinexor biomarker in lymphoma, that success will create pressure to test the drug in genotypes where no such biomarker exists, which is exactly the situation in acute leukaemia.
Still open
  1. Has C528S ever been observed in a patient progressing on selinexor? Nothing read in this beat reports it, and a common-essential covalent target with a known laboratory escape mutation is exactly where you would look.
  2. What are the novel cargoes of E571K? The change-of-function claim is directional in every source read here and the cargo list would make it testable.
  3. If mutant XPO1 is degraded faster and is therefore MORE drug-sensitive, is XPO1 protein turnover a general determinant of SINE response - including in wild-type cells with high XPO1 expression?
  4. Does the single XPO1 E571K B-ALL case in TARGET carry a KMT2A rearrangement? The cohort's fusion annotation is not exposed by the resource used here.
Every source behind this entry (5)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Whole-genome sequencing of chronic lymphocytic leukaemia identified XPO1 as one of four recurrently mutated genes, alongside NOTCH1, MYD88 and KLHL6, with NOTCH1 and XPO1 mutations mainly detected in patients with unmutated immunoglobulin genes, and with functional and clinical analyses indicating the recurrent XPO1 mutations are oncogenic changes contributing to clinical evolution.

    PMID 21642962DOI
    What this evidence cannot show

    CLL, adult mature B-cell disease - no relationship to this graph's index disease beyond the gene. Four genomes discovered the variants and 363 patients validated them; abstract-level for this beat. The abstract does not name E571 specifically; the hot-spot identity comes from E2 and E3.

    Evidence that argues against this (1)
    • PUBLISHED CONFLICTING RESULT on scope: the 'unmutated-IGHV CLL' framing is an artefact of which cohort was sequenced first. Liang et al. performed comprehensive genomic profiling on archival Hodgkin lymphoma and recovered XPO1 (E571) among the recurrently aberrant genes in a disease with a completely different cell of origin, microenvironment and neoplastic-cell fraction, then confirmed the mutation in plasma cell-free DNA in 31% of 13 tested patients with allele frequency tracking tumour size. The four CLL genomes that discovered the variant established recurrence in CLL, not the hot spot's disease distribution. Liang WS et al. 2019
  2. E2strong 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 highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing mis-localisation of critical regulators; in 1,286 CLL cases, 72 carried non-synonymous XPO1 mutations, which associated with high-risk genetic and epigenetic features and accelerated progression; B-cell expression of E571K or E571G with TCL1 accelerated leukaemogenesis in mice; and crystal structures of wild-type and E571K XPO1 bound to KPT-185, selinexor and eltanexor 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

    Abstract-level for this beat. Retrospective multi-centre series plus a transgenic mouse model plus crystallography - unusually complete for one paper, and all of it in CLL. 'Novel cargo-binding abilities' is asserted in the abstract without the cargo list, so the change-of-function claim is directional rather than specific here. The structural non-resistance conclusion is an inference from similarity of bound structures, not a measured IC50 shift in patient cells.

    Evidence that argues against this (1)
    • The change-of-function reading is weakened by the same abstract's statement that B-cell over-expression of WILD-TYPE XPO1 could also affect development of a CLL-like disease in aged mice, so part of the effect may be dose rather than novel cargo binding. And the hot spot is a mature-B-cell event: the founding CLL genome study placed it in unmutated-IGHV CLL, and no acute leukaemia cohort queried in this beat carries it at appreciable frequency. Puente XS et al. 2011
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma cells, XPO1 mutation renders lymphoma cells MORE sensitive to selinexor because mutant XPO1 is degraded faster than wild type, and mistrafficking of p65 (RELA) and p52 (NFKB2) between nucleus and cytoplasm accounts for the response to ibrutinib.

    PMID 36727672DOI
    What this evidence cannot show

    Abstract-level. Cell lines, mature B-cell lymphoma, adult disease. The faster-degradation explanation is mechanistically specific and would predict that mutation status is an ENRICHMENT biomarker for SINEs - the opposite of the usual assumption that a target-site mutation confers resistance. Worth noting that the NF-kB mistrafficking described here is the same phenomenon SET-Nup214 produces by tethering p65/IkB in the nucleus, reached by a different route.

    Evidence that argues against this (1)
    • PUBLISHED CONFLICTING RESULT on the direction, and it shows that XPO1 mutation status is not one biomarker but at least two. Neggers et al. engineered C528S - the SINE contact residue in the same NES-binding groove as E571 - into multiple leukaemia cell lines and showed a single HETEROZYGOUS substitution confers selinexor resistance as strongly as a homozygous one, i.e. dominantly. So within one groove, one residue's mutation is reported as an enrichment biomarker (E571, via faster degradation) and another's is a dominant resistance allele (C528). Any clinical use of 'XPO1-mutant' as a SINE biomarker must specify the codon, and this entry's title - 'it does NOT confer resistance to the drugs that bind the same groove' - is true of E571 and false of the groove. Neggers JE et al. 2016
  4. E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    CNS involvement by North American adult T-cell leukaemia/lymphoma was associated with discrete dissemination patterns and molecular profiles involving XPO1 E571 and KLF2/PIK3CD in selected cases.

    PMID 40712110DOI
    What this evidence cannot show

    TITLE-LEVEL ONLY; the abstract was not read in this beat. Recorded to show the hot spot is not confined to B-cell disease, and carried at weak confidence with nothing asserted beyond the title. 'In selected cases' in a title is a small-numbers signal.

    Evidence that argues against this (1)
    • METHODOLOGICAL DEFEATER for 'in selected cases', which is the load-bearing phrase in a title-level record. The same variant has been shown to behave as a tumour-burden marker: in Hodgkin lymphoma, XPO1 E571 mutant allele frequency in serially collected plasma corresponded with changes in tumour size on radiographic imaging. An association between XPO1 E571 and a dissemination pattern in selected cases is therefore confounded with disease burden and with the sampling that selected those cases, before any molecular-profile interpretation is reached. Recording this row as evidence that the hot spot is not confined to B-cell disease is reasonable; reading it as evidence of a distinct T-cell molecular programme is not. Liang WS et al. 2019
  5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Digital PCR assays were developed to detect XPO1 E571K alongside EZH2 Y641N and MYD88 L265P in plasma cell-free DNA from diffuse large B-cell lymphoma patients, with a sensitivity of 0.05%.

    PMID 26883583DOI
    What this evidence cannot show

    Abstract-level. A proof-of-concept assay paper, DLBCL, adult. Cited only to establish that E571K is treated as a recurrent actionable marker in mature B-cell lymphoma - the company it keeps (EZH2 Y641N, MYD88 L265P) is itself informative about which disease class this hot spot belongs to.

    Evidence that argues against this (1)
    • METHODOLOGICAL DEFEATER: a 0.05%-sensitivity genotyping assay reports presence, not function, and the function of an XPO1 coding change is residue-specific to the point of reversal. Neggers et al. showed that a single heterozygous C528S in the same cargo-binding pocket is sufficient and dominant for SINE resistance, while this entry's own E3 reports E571 mutation increasing SINE sensitivity. A ddPCR panel designed around E571K alongside EZH2 Y641N and MYD88 L265P therefore measures one codon and tells a clinician nothing about the drug-contact codon that would matter most if a SINE were being given. The company the assay keeps is informative about disease class, as the caveat says; it is not informative about actionability. Neggers JE et al. 2016
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