Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas.

T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that 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 chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.

Lumbar Spinous Process-Splitting Laminoplasty: A Novel Technique for Minimally Invasive Lumbar Decompression.

Minimally invasive posterior spinous process-splitting laminoplasty preserving the paraspinal musculature has been introduced to treat patients with lumbar spinal stenosis. Despite its theoretical advantage of limiting muscular trauma, additional efforts are required to evaluate patients' clinical and functional results following this procedure. Between 2010 and 2012, 37 patients underwent spinous process-splitting laminoplasty for lumbar stenosis at a mean age of 68 years (range, 36-87 years) and were followed for minimum of 1 year (mean, 1.3 years). There were 22 (59%) men and 15 (41%) women. Mean number of levels treated with a spinous process-splitting laminoplasty was 2.2 (range, 1-6 levels). Patients had statistically significant improvements in their scores for all self-reported outcomes, including visual analog scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), and Short Form 36 (SF-36) components. Mean VAS significantly decreased by 4.4±3.2 points for back pain and 3.9±3.7 points for leg pain (P<.0001). Mean ODI significantly decreased by 17.5±19.1 points (P<.0001), and mean SF-36 significantly increased by 29±30.4 points (P=.0017) for the physical component and 21.8±25.6 points (P=.0062) for the mental health component. Four (10.8%) patients had a dural tear requiring repair (3 were intraoperative), 3 (8%) had an epidural hematoma requiring evacuation, 1 (2.7%) had an infection requiring irrigation and debridement, and 2 (5%) had additional decompression for symptom recurrence secondary to instability. Lumbar spinous process-splitting laminoplasty is a novel minimally invasive technique that provides adequate decompression for the neuronal elements and may avoid extensive paraspinal muscular damage associated with conventional laminectomy. Patients demonstrated significant improvements in pain and overall heath and function scores at a minimum 1-year follow-up. [Orthopedics.2016; 39(5):e950-e956.].