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Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström's Macroglobulinemia, Mantle cell lymphoma, and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2−/− experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT (Signal Transducers and Activators of Transcription) signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage-mediated immune responses. [ABSTRACT FROM AUTHOR]

The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies. [ABSTRACT FROM AUTHOR]