[Frontiers in Bioscience 18, 371-386, January 1, 2013]

TLR9 signaling defines distinct prognostic subsets in CLL

Dimitar G. Efremov1, Riccardo Bomben2, Stefania Gobessi1, Valter Gattei2

Molecular Hematology, ICGEB, Campus A. Buzzati-Traverso, Rome, Italy, 2Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy


1. Abstract
2. Introduction
3. Response of CLL B cells to CpG-ODN stimulation in different prognostic subsets of CLL
4. Other external stimuli that induce variable responses in different prognostic subsets of CLL
5. TLR expression in CLL B cells
6. TLR signaling pathways in CLL cells
7. TLR9 stimulation induces distinct gene expression profiles in U-CLL and M-CLL cells
8. MicroRNAs regulate the proliferative response induced by TLR9 triggering
9. Role of TLR9 signaling in CLL pathogenesis
10. Conclusions
11. Acknowledgment
12. References


Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable clinical course. The behavior of the disease is believed to be influenced by microenvironmental signals that regulate the proliferation and survival of the malignant B-cells. Signals transduced through Toll-like-receptor-9 (TLR9) may play a particularly important role, as they could drive the expansion of a subset of cells that express B-cell receptors reactive with DNA or DNA-containing complexes. Interestingly, leukemic cells from patients with aggressive disease respond more effectively to TLR9 stimulation than their less aggressive counterparts, suggesting that the capacity to respond to TLR9 signals can define distinct prognostic subsets in CLL. The exact mechanism(s) accounting for the variability in the response to TLR9 engagement are still unclear, although important differences have been observed between prognostic groups in terms of downstream signaling events and gene- and miRNA-expression profiles. Understanding the mechanism(s) that underlie the different TLR9 responses should provide further insight in the pathophysiology of CLL and may lead to the identification of novel targets for therapeutic intervention.