This study aimed to determine whether the multi-kinase inhibitor dasatinib would 
provide an effective therapy for myeloproliferative diseases (MPDs) involving 
c-Cbl mutations. These mutations, which occur in the RING finger and linker 
domains, abolish the ability of c-Cbl to function as an E3 ubiquitin ligase and 
downregulate activated protein tyrosine kinases. Here we analyzed the effects of 
dasatinib in a c-Cbl RING finger mutant mouse that develops an MPD with a 
phenotype similar to the human MPDs. The mice are characterized by enhanced 
tyrosine kinase signaling resulting in an expansion of hematopoietic stem cells, 
multipotent progenitors and cells within the myeloid lineage. Since c-Cbl is a 
negative regulator of c-Kit and Src signaling we reasoned that dasatinib, which 
targets these kinases, would be an effective therapy. Furthermore, two recent 
studies showed dasatinib to be effective in inhibiting the in vitro growth of 
cells from leukemia patients with c-Cbl RING finger and linker domain mutations. 
Surprisingly we found that dasatinib did not provide an effective therapy for 
c-Cbl RING finger mutant mice since it did not suppress any of the hematopoietic 
lineages that promote MPD development. Thus we conclude that dasatinib may not 
be an appropriate therapy for leukemia patients with c-Cbl mutations. We did 
however find that dasatinib caused a marked reduction of pre-B cells and 
immature B cells which correlated with a loss of Src activity. This study is 
therefore the first to provide a detailed characterization of in vivo effects of 
dasatinib in a hematopoietic disorder that is driven by protein tyrosine kinases 
other than BCR-ABL.