Crosstalk between CLL and cutaneous T-cell lymphoma: MIF-CD74 axis and dysregulated inflammatory signaling

<h2>Abstract</h2><h3>Background</h3> The rare co-occurrence of chronic lymphocytic leukemia (CLL) and cutaneous T-cell lymphoma (CTCL) provides a unique model to study their interactions. Although CLL patients have a higher risk of secondary malignancies, its impact on CTCL remains unclear. <h3>Method</h3> To investigate this, we performed single-cell RNA, BCR and TCR sequencing (scRNA/V(D)J-seq) on lesional skin from two different subtypes of CTCL patients—one with Mycosis fungoides (MF) and one with Sézary syndrome (SS)—with concomitant CLL, as well as peripheral blood leukocytes (PBLs) from the SS patient. These were compared to five MF skin lesions and five SS PBLs without CLL. Cells were classified based on V(D)J sequencing and gene expression. Seurat, GSEA, and CellChat were used to analyze datasets. <h3>Result</h3> CLL infiltration was higher in MF (69.1%) than SS (6.8% in skin, 15.3% in PBL). Ex vivo scRNA-seq revealed distinct interactions between CLL cells and CTCL subtypes within their tumor microenvironments: TNF-α/NF-κB signaling and inflammation were suppressed in MF, but activated in SS, a trend also observed in SS/CLL's blood. Whereas CLL co-infiltration reduced programmed cell death (PCD) pathway (<i>GBP1, GBP5, CCL5, HPGD, FAS</i>) only in SS. Cell-cell interaction analysis highlighted the MIF-CD74 axis as central to CTCL-CLL crosstalk, with CTCL-derived MIF engaging CD74 on CLL cells. <h3>Conclusion</h3> These findings underscore the importance of microenvironmental crosstalk in shaping lymphoma progression and suggest subtype-specific therapeutic vulnerabilities. Further exploration of these interactions may inform strategies to disrupt pathogenic signaling networks in CTCLs.