Blood: TLR9, a new potential therapeutic target for chronic lymphocytic leukemia!

Although BCR targeted inhibitors revolutionized the treatment of chronic lymphocytic leukemia (CLL), CLL remains incurable.
suggests that other signaling molecules are involved in the immune escape mechanisms and drug resistance of CLL cells.
Tol-like subject 9 (TLR9) is a promising candidate, activated by unmedified CpG-DNA.
CLL patients with increased plasma cfDNA, associated with high CD38, short LDT, high leukemia burden and TTFT reduction Emma Kennedy, found that CLL patients' plasma contained significantly more unmedited DNA (p<0001) than healthy controlled plasma, and that free DNA (cfDNA) levels were associated with pre-labeled CD38, beta-2-microglobulin and lymphocyte multiplier time.
addition, elevated levels of free DNA were associated with a reduction in the time from the first treatment (TTFT: p=0.003, HR=4.0).
TLR9 expression can increase CD38, CD69 expression and cell migration and other events researchers also found that TLR9 expression is related to in-body CLL cell migration (p-lt;0.001), while introcyte TLR9 is closely related to abnormal expression of TLR9 (sTLR9) on the cell surface (r=0.9).
CLL cells from the source of the lymph nodes showed an increase in sTLR9 expression (p=0.016), and RNA sequencing of paired sTLR9hi and sTLR9lo CLL cells showed differential transcription of genes associated with TLR signal transducting, adhesion, movement and inflammation in STLR9hi cells.
blocking TLR9 reduces CLL cell migration in mechanisms, and TLR9 astrative ODN2006 promotes CLL cell migration mediated by p65 NF-kB and STAT3 transcription factor activation (p.lt;0.001).
importantly, the induced similar effects can be induced by the plasma and can be reversed by TLR9 antagonists.
, high TLR9 expression can promote the implantation of NSG mouse heterogeneity transplant model and the rapid development of disease.
In summary, this study shows that dual targeting of TLR9 and BTK has strong synergies, emphasizing the different roles of TLR9 signals in CLL and the potential of joint targeting of TLR9 and BTK as a more effective treatment strategy for CLL, an incurable disease.
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