Novel Cell Lines Identify Cell-Intrinsic and Targetable Features of Angioimmunoblastic T-Cell Lymphoma

Outcomes for patients with Nodal T-follicular helper lymphoma, angioimmunoblastic subtype (AITL) are poor compared to most B-cell Non-Hodgkin Lymphoma in part due to a dearth of pre-clinical models to guide development of novel therapeutic approaches. We have developed two unprecedented AITL cell lines through culture of cells from patient-derived xenograft models. Mutational profiling reveals that each cell line carries independent TET2 deleterious frameshift and stop-gain nonsense mutations, and neither produces detectable levels of Tet2 protein. We identified the characteristic AITL mutation RHOA G17V in one line but not the other, and this result combined with the TET2 loss-of-function mutations is consistent with the two most common genotypes identified in clinical AITL samples. RNA-seq analysis of AITL cell lines demonstrates enrichment in gene signatures driven by MYC, E2F, and enhanced metabolic demands, consistent with a malignant phenotype and shared with other T-cell Lymphoma (TCL) cell lines. Gene sets specifically enriched in AITL cell lines include inflammatory gene signatures as a defining feature, and assessment of media from cultured cells indicate that they secrete an abundance of cytokines that suggests primary malignant cells drive the inflammatory environment observed in clinical AITL samples. Using single-cell RNA-seq (scRNA-seq), we identified gene signatures enriched in individual primary malignant AITL cells compared to follicular-helper T cells (Tfh), which are the non-malignant counterpart of AITL. These signatures were also highly enriched in AITL cell lines compared to Tfh, validating both gene signatures from the scRNA-seq analysis and the AITL cell lines as consistent with a malignant AITL cell phenotype. We further confirmed enrichment of primary cell-intrinsic malignant gene expression in the AITL cell lines using a gene signature generated from an independent scRNA-seq analysis of AITL clinical samples. Finally, we performed functional studies that identify potentially translatable and targetable genetic vulnerabilities. Taken together this indicates that these novel AITL cell lines maintain genetic and transcriptomic fidelity to primary malignant AITL cells and that these models can be used to identify novel targeted therapeutic strategies for clinical studies of AITL.

No relevant conflicts of interest to declare.