XPO1 mutation

These results suggest that activation of autophagy confers a protective mechanism against Selinexor in GBM cells, and that the combination of Selinexor with autophagy inhibitors may serve as a viable means to enhance Selinexor-induced cell death.

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