We have characterized a tonically active B cell receptor signaling module of zap70+ve CLL cells that contributes to a high-risk disease phenotype associated with rapid tumor doubling time and cellular bcl-2 overexpression. In CLL cells, syk directs tyrosine phosphorylation of certain adaptors including cbl and crkL and this is also accompanied by tyrosine phosphorylation of the interdomain-B loop of zap70 to affect its own interaction with adaptors and vav1. Vav1 along with zap70 allows JNK activation and the formation of heightened c-jun/AP-1 involved in CLL cell bcl-2 transcription. However, CLL pathogenesis is equally dependent upon ezh2/PRC2-mediated 5′-methylation of CpG islands in several tumor suppressor genes such as PTPRO (a cell-intrinsic syk inhibitor) and DAPK1. In addition, ezh2 functions not only in the nucleus for gene repression, but in cytoplasm for stabilization/perpetuation of a zap70-vav1 signal complex upstream of JNK1 in lymphocytes (
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