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Jennifer R. Brown, MD, PhD


Does Interleukin 9 Play a Role in the Pathogenesis of CLL?

By: Gavin Calabretta, BS
Posted: Tuesday, February 8, 2022

Interleukin 9 (IL-9) is suspected to contribute to the development of chronic lymphocytic leukemia (CLL), but the concrete mechanism by which this occurs is unknown. Providing a closer look into what is understood about IL-9, Cosima T. Baldari, PhD, of the University of Siena, Italy, and colleagues published a review article in Cancers, summarizing the cytokine’s prognostic role in different tumor subtypes.

According to the study authors, cytokines are known to be “dual players.” They target immune and nonimmune cells, activating signaling cascades that may induce an antitumor response in some malignancies—yet, by contrast, a protumor response in others. Specifically, CLL B cells contribute to an altered cytokine balance in which tumorigenesis is promoted and apoptosis hampered. IL-9 itself has shown protumoral activity in this context.

In leukemic cells, overexpression of IL-9 has correlated with signs of aggressive disease, including unmutated IHVG and high levels of the surface glycoprotein CD38. Overexpression of IL-9 also seems to correlate with lower overall survival in patients with CLL, and a link between Th9 cell–secreted IL-9 and oxidative stress has been found. Although the exact mechanisms of IL-9 are up for debate, certain studies have demonstrated that transcription factors STAT6 and STAT3 are implicated in the regulation of IL-9 expression. Particularly, STAT3 activation upregulates miR-155 and miR-21 expression in CLL cells, which consequently promotes IL-9 expression. In addition, transcription factor NF-κB also regulates IL-9 expression in T cells and mast cells, and a similar mechanism is believed to exist in B cells. This hypothesis is supported by the fact that NF-κB is constitutively active in CLL B cells. Lastly, IL-9 overexpression has shown a strong inverse relationship with the proapoptotic adaptor p66Shc.

Although IL-9 has exhibited protumoral activity in hematologic malignancies like CLL, in contrast, it has exhibited antitumoral activity in solid tumors, such as melanoma and certain gastric cancers.

Disclosure: The study authors reported no conflicts of interest.

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