XPO1 mutation

This iPSC line was facilitated through the use of episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, and human miR-302. The SYSUSHi001-A iPSC line exhibited characteristic embryonic stem cell-like morphology, maintained the XPO1 and PALB2 mutations, expressed key pluripotency markers, preserved a normal karyotype (46, XY), and demonstrated the ability to differentiate into cells from all three germ layers in vitro.

To do so we generated glioblastoma and patient-derived glioblastoma xenograft cells that express either endogenous wild-type (WT) XPO1 or endogenous WT XPO1 plus a doxycycline-inducible point-mutant form of XPO1 (C528S) that exhibits full XPO1 activity but cannot bind or be inhibited by Selinexor. Furthermore, the resistance provided by prolonged expression of C528S, or by shRNA-mediated suppression of XPO1 levels, was nearly 10-fold less than that provided by complete CRISPR-based replacement of WT XPO1 with C528S. These results therefore show that a transient suppression of XPO1 activity is sufficient for Selinexor-induced cytotoxicity in glioblastoma cells, and suggest that the Selinexor-induced lethality results from a combination of loss of XPO1 activity and Selinexor-XPO1 complex formation.

The reported low TMB in CLL does not reflect the true frequency of neoantigens, as it fails to account for BCR neoantigens. These contribute ~80% of the neoantigen pool and are predominantly presented by HLA-II. The majority of BCR neoantigens in M-CLL are within the V region, whereas in U-CLL, BCR neoantigens are largely restricted to the V(D)J recombination site.

We found co-occurrence of inactivating events in A20 and XPO1 missense mutations impacting 15% of PMBCL evaluated cases, with consistent results seen across all studies (range: 13.8-20%). As expected, A20 mutations/del were more prevalent than XPO1 mutations across all studies (OR 2.46, 95% CI 0.84-7.18, p = 0.02). XPO1 mutated cases trended towards a greater likelihood of having co-occurring A20 mutations (OR 8.51, 95% CI 0.84-86.47, p = 0.08).

IGLV3-21R110 was identified as an independent prognostic factor for shorter EFS in early stage CLL with intermediate/high risk score and was associated with reduced ibrutinib efficacy in the CLL12 trial.

Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic syndrome (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations...Using the Bliss independence model to calculate synergy, we identifed two drugs that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and navitoclax (a BCL2/BCL-XL inhibitor)...Our findings may also contribute to the development of potentially synergistic therapeutic combinations. In this regard, recent human data have shown that venetoclax can overcome the poor prognosis of spliceosomal mutant AML patients (Senapati et al, Blood 2023); therefore, combining eltanexor with venetoclax could represent a promising SF3B1-specific therapy.

Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is another NPM1 "born to be exported" mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novel NPM1 mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.

Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL.

73 patients had only one BTKi (ibrutinib (IBR), 64; acalabrutinib (ACA), 9). 12 pts had multiple BTKis, 8 with two drugs with IBR first followed by ACA (Nf3, 37.5%), vecabrutinib (Nf1, 12.5%), and PIR (Nf4, 50.0%); and 4 with three or more drugs... Our retrospective report summarizes mutations detected during BTKi treatment and shows that BTK L528W can occur during both covalent and non-covalent BTK inhibitor therapy. Four of six patients who progressed on PIR had T474 mutations. In addition, our results may suggest that activating mutations in RAS/RAF/MAPK pathway are related to BTKi resistance.

These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signaling leading to higher proliferation and shorter TTFT in early stage CLL.

P2, N=36, Recruiting, Memorial Sloan Kettering Cancer Center

These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signaling leading to higher proliferation and shorter TTFT in early stage CLL. Chronic lymphocytic leukemia, B cell chronic lymphocytic leukemia

This study highlights scRNA-seq as an efficient method for tracking rare cells potent for causing CLL refractoriness, thus enabling their subsequent detailed characterization. Presented study was funded by the following grants: MH-CZ_AZV_NU20-08-00314, MEYS- CZ_MUNI/A/1224/2022, MH-CZ_RVO_65269705009, NPO_NUVR_LX22NPO5102, TACR_TN02000109. TP53, RNA-seq, B-CLL

HSP110 is an essential protein for PMBL and cHL cell survival, through its interaction with STAT6 and its requirement for STAT6 phosphorylation. HSP110 is a cargo protein of XPO1 which is also required for STAT6 phosphorylation. HSP110 inhibitor and selinexor have a synergistic effect in reducing tumour growth, suggesting that this combination could be a promising new therapeutic strategy for PMBL and cHL.

"XPO1 inhibition with selinexor synergized with chemotherapy in XPO1 R749Q mt cells in vitro and overcame resistance to irinotecan in vivo in xenograft mice models. This study sheds novel insights into the role of nuclear export in cancers. This study sheds novel insights into the role of nuclear export in cancers. Specifically, XPO1 R749Q mutations are enriched in TMB-H endometrial and colon cancers and increase nuclear export of key proteins that confer resistance to therapies using DNA-damaging agents. Our current work aims to identify novel therapies that can overcome resistance to DNA-damaging therapies seen in XPO1 mutant cells, such as immune checkpoint inhibitor (ICI) therapy given the co-occurrence with POLE mutations and recent reports of high level of response to ICI therapy in TMB-H and POLE mt colorectal cancers."

To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response towards ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B-cell hemopathies to SINEs and drugs that target even indirectly the NFκB signaling pathway.

While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

These findings are of special interest in case 12, because our PDX was primary resistant to ibrutinib and the original CLL sample was sensitive to the drug, suggesting that resistance to this drug may be acquired independently of its exposure. Finally, we observed that RT cells were resistant to venetoclax, but this resistance could be circumvented by the incubation of cells in combination with the OXPHOS inhibitor IACS-010759...We propose that targeting OXPHOS in combination with venetoclax might be a potential targeted therapy in RT patients. Altogether, these models will facilitate the development of new therapeutic opportunities for patients with RT.

The combination of selinexor and irinotecan showed high levels of synergy in vitro. Our study established the biological and mechanistic consequences of XPO1 R749Q mutations in cancer, thereby having a significant positive impact on the treatments of patients with cancer. Further work is ongoing for the identification of cargo proteins transported by mutated XPO1 that connect the effects of XPO1 R749Q mutation on nuclear export to response to DNA damage, mTOR signaling and XPO1 inhibition in tumors in vitro and in vivo.

It was also found that XPO1 inhibited the activity of immune cells in the tumor immune microenvironment, such as CD8+ T cells, and affected biological pathways, such as the cell cycle and oxidative phosphorylation, and drove the expression of cancer driver genes, immune checkpoint genes, and highly mutated genes. XPO1 is a potential pan-cancer risk factor as it may jointly promote tumor onset and progression by inhibiting the immune response, influencing relevant biological pathways, and promoting mutations in other genes.

Although CNS involvement in NA-ATLL portends a poor prognosis, a sizable number of patients can be offered allogeneic grafting as a safe and potentially curative treatment.

The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months)... Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells.

Significance : We report that simultaneous disruption of essential regulators XPO1 and A20 in murine B cells encourages development of irregular B and T cell populations, and can stimulate a progressive CLL-like or T cell leukemia-like expansion. Continued investigation with these models can further our understanding of the relationship between overall immune function and these critical regulatory molecules, and can provide considerable insight to identifying pathways for selective targeting as a personalized therapy in several high-risk cancer types.

No abstract available

XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

Our results also suggested that lenalidomide might relieve relapsed lymphoma with mutations in NFKBIA 202C>T (p.Q68*) and NFKBIE 433A>T (p.K145*) by targeting NF-Kappa B signaling. In addition, the inhibitor selinexor may be another choice for refractory or relapse (r/r) DLBCL patients after CAR-T cell treatment...In this work, we demonstrated the use of serial ctDNA monitoring in r/r DLBCL patients after CD19-targeted CAR-T cell therapy. Our longitudinal NGS profiling revealed the changes of ctDNA mutation in accordance with prognosis, and shed some light on exploring more targeted treatment options together with CAR-T cell therapy.

Conclusion Based on these results, we conclude that SF3B1, EGR2, XPO1 and BIRC3 mutations independently predicted short TTFT and should be considered for extended molecular testing in CLL. However, considering the different impact of gene mutations in M-CLL and U-CLL, the IGHV mutation status must be taken into account when constructing future prognostic models including recurrent gene mutations.

Presence of XPO1 pathogenic mutations was associated with a poor survival in both the entire NSCLC cohort and the adenocarcinoma subgroup . Further studies of this negative association at the molecular level along with effect of other co-existing mutations can result in development of novel treatment strategies.

We therefore hypothesized that combining selinexor and venetoclax would have potential synergy and could be used to target hematologic malignancies bearing XPO1 and SF3B1 mutations.We first determined whether XPO1 and SF3B1 mutant cell lines showed differential response to either selinexor or venetoclax monotherapy. This combination is highly promising as an all oral regimen for hematologic malignancies bearing these mutations. Further, preclinical testing in in vivo using XPO1 and SF3B1 mutant and wildtype mice is ongoing.