Cas-L Suppresses Progression of Leukemia Induced by p210Bcr/Abl.

Cas-L (Crk-associated substrate lymphocyte type) which is also known as Hef1/Nedd9 was first identified as a protein tyrosine-phosphorylated upon stimulation of β1 integrin in peripheral T cells. Cas-L is a member of Cas family proteins, with a single Src homology (SH) 3 domain and multiple YXXP motifs (substrate domain) and functions as a docking protein in focal adhesions. Bcr/Abl is a fusion oncoprotein that induces chronic myelogeneous leukemia and acute lymphoblastic leukemia. Previous studies reported that Cas-L is tyrosine-phosphorylated by p190Bcr/Abl in lymphoid cells. In this study, we found that Cas-L is also expressed in myeloid cells, which suggests functional interaction between CasL and p210Bcr/Abl. To elucidate the role of Cas-L in leukemia induced by p210Bcr/Abl, we generated the Cas-L-deficient p210Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative disease compared with the p210Bcr/Abl transgenic mice, which results in the early death of those mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas-L. No significant differences were detected in the proliferation assay using bone marrow cells from those mice. Taken together, Cas-L seems to negatively regulate the progression of p210Bcr/Abl-induced leukemia presumably by inhibition of extramedullary hematopoiesis.