Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas

T cell leukemia/lymphoma 1 (TCL1) is an oncogene over-expressed in T-cell prolymphocytic leukemia (T-PLL) and in B-cell malignancies including B-CLL and lymphomas. To date, only a limited number of Tcl1 interacting proteins that regulate its oncogenic function have been identified. Prior studies utilized a proteomic approach to identify a novel interaction between Tcl1 with Atm (Ataxia Telangiectasia Mutated). The association of Tcl1 and Atm leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with Hsp70. The Tcl1-Hsp70 complex was validated by co-immunoprecipitation experiments. Also, we report that heat shock protein 70 (Hsp70), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for CLL and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.