Fig. 1: Proposed pathogenetic model of CAR+ T-cell lymphomas.

Suggested trajectories towards CAR+ T-cell lymphoma in the context of pre-existing clonal hematopoiesis of indeterminate potential (CHIP) based on published cases. A mutation in an epigenetic regulator, most commonly TET2 or DNMT3A (yellow asterisk), arises at low frequency in the hematopoietic stem cell compartment. This CHIP-associated alteration leads to a ‘burdened’ myeloid and B-cell lineage, the latter of which potentially even giving rise to the initial B-cell malignancy for which the CAR-T cell therapy was intended. Simultaneously, these precursor lesions can create a permissive T-cell compartment. Following genomic integration of the CAR vector, selective expansion of the mutated T-cell clone occurs, driven by persistent antigenic stimulation, potentially through the CAR’s own target, such as soluble BCMA (sBCMA). The CAR itself thus functions as a continuous signaling driver [24], promoting uncontrolled T-cell proliferation. Additionally, secondary genomic events (red asterisk), such as mutations in JAK or MAPK signaling pathways, further enhance pro-survival and proliferative signaling. Disruptions in DNA damage regulators, exemplified by CHK2, may contribute to genomic instability, facilitating full malignant transformation. To date, genomic CAR integration into a well-established cancer-associated gene has been demonstrated in a single case of CAR+ T-cell lymphoma, in which a monoallelic insertion into the TP53 gene potentially contributed to malignant transformation. Created in BioRender (https://BioRender.com/f50a476).