Differential genomic and transcriptomic events associated with high-grade transformation of Chronic Lymphocytic Leukemia

Klintman, Jenny; Stamatopoulos, Basile; Ridout, Katie; Eyre, Toby A.; Pascua, Laura Lopez; Appleby, Niamh; Knight, Samantha Jl; Dreau, Hélène; Popitsch, Niko; Ehinger, Mats; Martín‐Subero, José I.; Campo, Elı́as; Månsson, Robert; Rossi, Davide; Taylor, Jenny C; Vavoulis, Dimitrios V; Schuh, Anna

doi:10.1101/644542

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References 60 publications

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“…Those affecting XPO1 are primarily observed as single point mutations to a residue within the NES-binding groove (most frequently E571K or E571G), altering the charge and structural basis of the amino acid in this critical location [25]. These recurrent hot-spot point mutations have been reported in ~ 5% of CLL cases and between ~ 25 and 35% of CLL cases progressing to RT, suggesting either a pathogenic role for this genetic aberration or association with other high risk features [24,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

et al. 2021

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Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Methods We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). Results We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. Conclusions These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

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