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. 2021 Jan 15;14:17. doi: 10.1186/s13045-021-01032-2

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — E571 XPO1 mutations occur in CLL and disrupt the transcriptome of the CLL cell. Structure of wildtype XPO1 (grey surface; RanGTP and RanBP1 in the complex are not shown for clarity) with an NES peptide (green cartoon) bound in NES-binding groove, which is located on the convex side of the protein between HEAT repeats H11 and H12. Details of the boxed area is shown in the bottom left panel: the NES peptide, Mek1^NES, binds close to (3.4 Å) the side chain of E571 of wildtype XPO1. Bottom right: the E571K mutation places a lysine at position 571, which makes electrostatic interactions with a glutamate side chain of Mek1^NES causing the NES to bind much tighter to the XPO1 mutant [50]. Due to its simplicity, interactions with the E571G mutation are not shown. a Violin plot depicting the variant allele frequency (VAF) in CLL patients with an E571 XPO1 mutation. A median VAF of 0.47 (25th percentile = 0.39, 75th percentile = 0.50) suggests the heterozygous E571 XPO1 mutation is present in the dominant clone in these patients. Fewer than 5 XPO1-mutated CLL cases presented a VAF < 0.20. b Multidimensional scaling (MDS) plot of the top 1000 most variable genes in CLL cells isolated from patients with (E571K; n = 3) and without (WT; n = 4) an E571K XPO1 mutation demonstrate distinct clustering between mutated and non-mutated CLL samples along MDS dimension 1. c Volcano plot depicting adjusted p-values (FDR) versus log twofold change between E571K XPO1 and WT XPO1 IGHV-U CLL samples. Differentially expressed genes were selected with a fold change cutoff of 4 at 5% FDR. Significant genes enriched in E571K-mutated CLL cell samples are shown in red, and significant enrichment of genes in wt-XPO1 CLL cell samples are shown in blue. Along with upregulation of known supportive oncogenes, E571K XPO1 mutated CLL samples appear to demonstrate an increase in T cell-specific genes. d Heat map demonstrating differential expression of genes (|FC|> 4, FDR < 0.05) between E571K XPO1 (n = 3) and WT XPO1 (n = 4) IGHV-U CLL samples. Genes of interest are labeled. e Ingenuity Pathway Analysis (IPA) software analysis using significant differentially expressed genes in E571K XPO1 mutated CLL samples reveals perturbed downstream pathways enriched in T cell-related signaling and proliferation pathways. Enriched pathways are sorted by –Log(p value)