Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia

Abstract

Interleukin (IL)-9 is a soluble factor secreted by immune cells into the microenvironment. Originally identified as a mediator of allergic responses, IL-9 has been detected in recent years in several tumor niches. In solid tumors, it mainly promotes anti-tumor immune responses, while in hematologic malignancies, it sustains the growth and survival of neoplastic cells. IL-9 has been recently implicated in the pathogenesis of chronic lymphocytic leukemia; however, the molecular mechanisms underlying its contribution to this complex neoplasia are still unclear. Here, we summarize the current knowledge of IL-9 in the tumor microenvironment, with a focus on its role in the pathogenesis of chronic lymphocytic leukemia.

Keywords: CLL; IL-9; cytokine; hematologic malignancies; tumor microenvironment.

Figure 1

IL-9 Signaling Pathways. IL-9 binds to the heterodimeric receptor IL-9R and recruits the Janus kinases JAK1 and JAK3. The phosphorylated JAKs activate the STAT1 and STAT5 homodimers and the STAT1:STAT3 heterodimer, which translocate into the nucleus and bind DNA to control gene expression. JAK1 also activates IRS-1, which, in turn, activates the PI3-K/Akt-dependent anti-apoptotic pathway, and the Ras/MAPK signaling pathway that controls gene expression.

Figure 2

IL-9 expression and functions in CLL. IL-9 expression in CLL B cells is positively regulated in the following ways: (i) by the binding of IL-4 to the IL-4 receptor IL-4R and STAT6 activation; (ii) by the defective expression of p66Shc and the resulting low levels of intracellular ROS; and (iii) by a positive feedback loop activated by IL-9 secreted by CLL B cells themselves, which binds IL-9R and activates STAT3. IL-9 also acts on stromal cells, enhancing the expression of homing chemokines that, in turn, act on CLL B cells to promote their homing to lymphoid organs. ROS: reactive oxygen species.