Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors 
for proliferation and survival. In particular, the B-cell receptor (BCR) and 
nuclear factor- κB (NF-κB) pathways are activated in the lymph node (LN) 
microenvironment. Thus, model systems mimicking tumor-host interactions are 
important tools to study CLL biology and pathogenesis. We investigated whether 
the recently established NOD/scid/γc(null) (NSG) mouse xenograft model can 
recapitulate the effects of the human microenvironment. We assessed, therefore, 
tumor characteristics previously defined in LN-resident CLL cells, including 
proliferation, and activation of the BCR and NF-κB pathways. We found that the 
murine spleen (SP) microenvironment supported CLL cell proliferation and 
activation to a similar degree than the human LN, including induction of BCR and 
NF-κB signaling in the xenografted cells. Next, we used this model to study 
ibrutinib, a Bruton's tyrosine kinase inhibitor in clinical development. 
Ibrutinib inhibited BCR and NF-κB signaling induced by the microenvironment, 
decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. 
Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, 
recapitulate the role of the human LN for CLL cells. In addition, we show that 
ibrutinib effectively disrupts tumor-host interactions essential for CLL cell 
proliferation and survival in vivo.