XPO1 mutations identify a subgroup of early stage CLL patients characterized by shorter time to first treatment conceivably due to enhanced B cell receptor signaling

Most early-stage chronic lymphocytic leukemia (CLL) patients do not require immediate treatment and are actively managed with watch & wait strategy. While few clinical and molecular factors predict treatment requirement, the impact of gene mutations in unknown. In this study, we examined a total of 1092 early- stage CLL cases, subdivided into a training group (N=295) and two validation cohorts (N=402 and N=395). Through NGS analysis, we identified XPO1 mutations as predictor of shorter time to first treatment (TTFT). Importantly, XP01 mutations retained their prognostic significance independently of IGHV status and variables incorporated into the prognostic models that predict TTFT in early-stage CLL (IPS-E and Rai O Model). To elucidate the mechanisms underlying the higher proliferation rate of XPO1 mutated cells, we conducted RNA and ATAC-seq on 8 XPO1-mutated CLL samples and 15 XP01 wild-type CLL cases, matched for IGHV status, FISH karyotype, and TP53 status. The analysis revealed that chromatin regions with increased accessibility in XP01-mutated CLL were enriched with binding sites for transcription factors regulated by BCR-related pathways, including NF-kB signaling, p38-JNK, and RAS-RAF-MEK-ERK. Pathway enrichment analysis of upregulated genes from RNA-seq data indicated that XP01 mutant CLL exhibited transcriptomic features associated with BCR and cytokine signaling. Combining epigenomic and transcriptomic data, we found that MIR155HG (the host gene of miR-155) and MYB (the transcription factor regulating MIR155HG) were upregulated, and their promoters were more accessible in XPO1-mutated CLL. Further confirmation through RT-qPCR demonstrated higher expression of miR-155 in XP01-mutated cells. In conclusion, XP01 mutations, conceivably by increasing miR-155 levels, enhance BCR signaling, resulting in a higher proliferation rate and a shorter TTFT in early-stage CLL. The integration of XPO1 mutations into existing scoring systems may aid in identifying patients who would derive the greatest benefit from early intervention clinical trials.