IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3

The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, thereby advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required. B cells were isolated from bone marrow of 1 month old C57Bl/6 mice with genotype IL6+/+, IL6-/-, IL6+/+;EuMyc transgene, or IL6+/+; EuMyc transgene. Samples were pools from 3-5 mice and RNA was isolated by miRNeasy from Qiagen and analyzed by the Stony Brook University Affymetrix core facility. The Affymetrix GeneChip miRNA 4.0 array was used. Hierarchical clustering and pairwaise comparison between B cell populations was performed.