TMD8 Cells

The TMD8 cell line is a human diffuse large B-cell lymphoma (DLBCL) model representative of the activated B-cell-like (ABC) subtype. This subtype is characterized by constitutive activation of the NF-κB pathway, which is essential for cell survival. TMD8 exhibits wild-type CARD11, yet maintains strong NF-κB activity, indicating a dependency on chronic active B-cell receptor (BCR) signaling. This dependency is supported by experimental evidence showing that knockdown of BCR pathway components—including BTK, CD79A, CD79B, and IgM—leads to cell death in TMD8 cells. Additionally, TMD8 harbors a Y196H mutation in the ITAM domain of CD79B, a mutation commonly found in ABC-DLBCLs that enhances surface BCR expression and attenuates negative feedback from Lyn kinase, thus promoting sustained signaling activity.

TMD8 cells also demonstrate notable sensitivity to BCL-2 inhibition via venetoclax when expressing high levels of the BCL-2 protein. However, resistance to venetoclax in such cells can be mediated by activation of the PI3K/AKT pathway, particularly following prolonged drug exposure. This resistance mechanism involves a reduction in PTEN expression and increased AKT phosphorylation. TMD8 cells with acquired resistance to venetoclax exhibit heightened susceptibility to pharmacological PI3K/AKT pathway inhibition, making them a suitable model for studying therapeutic combinations aimed at overcoming resistance in aggressive B-cell lymphomas.