AUTHOR=Spaner David E. , Luo Tina YuXuan , Wang Guizhi , Schreiber Gideon , Harari Daniel , Shi Yonghong 

TITLE=Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1043694

DOI=10.3389/fonc.2023.1043694

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials.</p></sec><sec><title>Methods</title><p>The effect of ruxolitinib on primary human CLL cells was studied <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Results</title><p>Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells <italic>in vitro</italic>. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited  TLR-mediated <italic>IL10</italic> transcription and markedly reduced IL-10 production <italic>in vitro</italic>. It also decreased blood levels of IL-10 while increasing TNFα along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells <italic>in vivo</italic>. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production <italic>in vitro</italic> but, in contrast to ruxolitinib, blocked initial <italic>IL10</italic> transcription induced by TLR-signaling in vitro, decreased TNFα production, and deactivates CLL cells <italic>in vivo</italic>.</p></sec><sec><title>Discussion</title><p>These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFκB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL.</p></sec>