TLR9-dependent migration identifies different Chronic Lymphocytic Leukemia signaling states under BTK inhibition.

TLR9-driven migration reveals two distinct CLL signaling states, with 52% maintaining migration despite BTK inhibition, indicating BTK-independent pathways.

• Why it matters: Understanding mechanisms behind incomplete responses and resistance to BCR inhibitors in CLL is crucial for developing effective treatments, especially when BTK mutations are absent.
• What they did: Analyzing 102 patient samples, the study identified two phenotypes based on TLR9-induced migration and signaling: Responders with intact TLR9 pathways and Reverse-Responders with suppressed TLR9 signaling, using transcriptomic, protein, and in-silico modeling methods.
• The result: TLR9-induced migration persisted in the R subgroup despite BTK inhibition, suggesting alternative pathways, and samples from BTKi-resistant patients showed increased TLR9 expression and NF-kB signaling, highlighting potential targets for overcoming resistance.