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

Center point:

Center point:

The expression of TLR9, its agonist, and free plasma DNA are all related to the accelerated metastasis and poor prognosis of CLL
.

The expression of TLR9, its agonist, and free plasma DNA are all related to the accelerated metastasis and poor prognosis of CLL
.

The dual targeting of TLR9 and BTK can synergistically inhibit the migration of CLL cells and block the activation of p65 NF-κB and pSTAT3
.

The dual targeting of TLR9 and BTK can synergistically inhibit the migration of CLL cells and block the activation of p65 NF-κB and pSTAT3
.

Although B-cell receptor targeting inhibitors have completely changed the treatment of chronic lymphocytic leukemia (CLL), CLL is still incurable, suggesting that there are other signaling molecules involved in the escape mechanism and drug resistance of CLL
.

Toll-like receptor 9 (TLR9) can be activated by unmethylated cytosine guanine dinucleotide DNA and is a promising candidate target for CLL treatment
.

Toll-like receptor 9 (TLR9) can be activated by unmethylated cytosine guanine dinucleotide DNA and is a promising candidate target for CLL treatment
.

Correlation between plasma free DNA and time before first treatment

Correlation between plasma free DNA and time before first treatment

Kennedy et al.
found that compared with healthy control subjects, the plasma of CLL patients contained significantly more unmethylated DNA (p<0.
0001); they also found that the level of free DNA is correlated with the prognostic markers CD38 and β2-microspheres.
Protein is related to lymphocyte doubling time
.

In addition, the increase in free DNA is also related to the shorter time before the first treatment (hazard ratio 4.

Compared with healthy control subjects, the plasma of CLL patients contains significantly more unmethylated DNA.

TLR9 expression is related to the migration of CLL cells in vitro ^{hi lo hi}

In terms of mechanism, the TLR9 agonist ODN2006 can promote the migration of CLL cells (p<0.
001), which is mediated by the activation of p65 NF-κB and STAT3 transcription factors
.

Importantly, autologous plasma can induce the same effect, which can be reversed by TLR9 antagonists

TLR9 agonist ODN2006 can promote CLL cell migration

Blocking TLR9 can inhibit CLL cell migration and has a synergistic effect with ibrutinib

Blocking TLR9 can inhibit CLL cell migration and has a synergistic effect with ibrutinib

In addition, in the NOD/Shi-scid/IL-2Rγ ^null mouse xenograft model, high TLR9 expression can promote tumor transplantation and rapid progress
.

Finally, the researchers also demonstrated that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) has a strong synergistic effect, highlighting the different roles of TLR9 signaling in CLL, and the potential therapeutic value of combined targeting of TLR9 and BTK

^null dual targeting TLR9 and Bruton tyrosine kinase (BTK) has a strong synergistic effect, which emphasizes the different roles of TLR9 signaling in CLL, and the potential therapeutic value of combined targeting TLR9 and BTK

Original source:

Original source:

Emma Kennedy, et al.

TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target in this message