In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) 
play a major role in disease development and progression. In this light, new 
therapies that specifically target signaling molecules downstream of the BCR 
continue to be developed. While first studies on the selective small molecule 
inhibitor of Bruton's tyrosine kinase (Btk), Ibrutinib (PCI-32765), demonstrated 
that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory 
behavior, these studies however did not address whether Btk-mediated signaling 
is involved in the process of CLL leukemogenesis. To investigate the requirement 
of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ 
CLL mouse model, which is based on sporadic expression of the simian oncovirus 
SV40 T-antigen in mature B cells. To this end, we crossed IgH.ETμ mice on a 
Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here 
we show that Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and 
that leukemias formed in Btk haplo-insufficient mice selectively expressed the 
wild-type Btk allele on their active X chromosome. Conversely, Btk 
overexpression accelerated CLL onset, increased mortality, and was associated 
with selection of non-stereotypical BCRs into CLL clones. Taken together, these 
data show that Btk expression represents an absolute prerequisite for CLL 
development and that Btk mediated signaling enhances leukemogenesis in mice. We 
therefore conclude that in CLL Btk expression levels set the threshold for 
malignant transformation.