In addition to their canonical role in activating transcription factors of the STAT family, Janus kinases (JAKs) also phosphorylate histones, influencing gene expression through chromatin modification. Both STAT signaling and JAK-mediated histone modifications are dysregulated in several lymphomas. Rui et al. found that the activated B cell–like subtype of diffuse large B cell lymphoma (ABC DLBCL), an aggressive lymphoma with a low rate of cure, depends on the JAK1-mediated phosphorylation of histone 3 for malignancy and showed that the combination of a JAK1 inhibitor with an existing lymphoma drug more effectively killed the lymphoma cells. ABC DLBCL cells require autocrine signaling by the cytokines interleukin-6 (IL-6) and IL-10, which promotes STAT3 production, for their survival. To understand the role that JAKs play in producing the malignant phenotype, the authors compared signaling pathways between ABC DLBCL cells and a less aggressive subtype, germinal center B cell–like DLBCL cells (GCB DLBCLs). Pharmacologically inhibiting JAK1 with the compound AZD1480 reduced the survival of ABC DLBCL cells but not GCB DLBCL cells. However, overexpressing a constitutively activated form of STAT3 in JAK1-deficient ABC cells only partially rescued cell survival, whereas ectopic expression of JAK1 restored viability, indicating that the role of JAK1 was not solely due to its phosphorylation of STAT3. JAK1 was detected in the nuclear fractions of the ABC DLBCL cell lines HBL1 and TMD8, and knockdown of JAK1 resulted in a reduction in the abundance of the cell cycle–regulating transcription factor MYC, similarly to a noncanonical effect of JAK2 in other types of lymphomas. Inhibition of JAK1 decreased the overall phosphorylation of tyrosine 41 of histone 3 (H3Y41). Chromatin immunoprecipitation with sequencing (ChIP-Seq) analysis revealed that most of the phosphorylated H3Y41 sites were associated with the promoters of protein-encoding genes. Of the H3Y41 sites whose phosphorylation was reduced by AZD1480, less than 10% were in a STAT-binding region. Gene expression analysis showed that those genes that showed reduced expression in response to AZD1480 overlapped significantly with those with JAK1-dependent H3Y41 phosphorylation, suggesting that JAK1-dependent chromatin modification induces expression of these genes. Some of these included genes that play roles in ABC DLBCL pathology, such as myc, myd88, and irf4. MYD88 signaling to the nuclear factor κB pathway leads to the production of IL-6 and IL-10, which activate JAK1. Thus, the JAK1-dependent increase in myd88 expression could be part of a positive feedback loop of activation. IRF4 is a transcription factor that is activated by B cell receptor (BCR) signaling downstream of the BCR-activated tyrosine kinase BTK. AZD1480 in combination with ibrutinib, a BTK inhibitor, caused more cell death than did either compound alone in two ABC DLBCL cell lines. Thus, JAK-mediated epigenetic regulation may provide an additional target for the treatment of malignant lymphomas. Further investigation would be required to identify how JAK-mediated modification of chromatin differs in healthy and cancerous cells.
L. Rui, A. C. Drennan, M. Ceribelli, F. Zhu, G. W. Wright, D. W. Huang, W. Xiao, Y. Li, K. M. Grindle, L. Lu, D. J. Hodson, A. L. Shaffer, H. Zhao, W. Xu, Y. Yang, L. M. Staudt, Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. U.S.A. 113, E7260–E7267 (2016). [PubMed]