Transducin ß-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin ß-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signalling pathway by binding to ß-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B-cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, ß-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.

Examining the contributions of desirable difficulty and reminding to the spacing effect.

Although substantial evidence indicates that spacing repeated study events with intervening material generally enhances memory performance relative to massing study events, the mechanism underlying this benefit is less clear. Two experiments examined the role of reminding difficulty during the acquisition of material in modulating final memory performance for spaced repetitions utilizing recognition (Experiment 1) and recall tests (Experiment 2). Specifically, participants studied a list of words presented one or two times separated by one or five items. On each trial participants reported whether the item had been previously presented (i.e., repetition detection judgment), and the response latency served as a proxy for reminding difficulty such that longer response latencies reflected more difficult reminding. A third experiment extended this paradigm with the inclusion of a massed condition and novel lag conditions (three and ten items). Results revealed significant lag effects in final test performance across experiments despite comparable repetition detection difficulty between lag conditions during acquisition. Moreover, results from within-participant point-biserial analyses and mediation analyses converged on overall performance measures in suggesting that repetition detection difficulty failed to modulate final test performance in the current paradigm. Discussion considers the implications of the current results for mechanisms proposed to underlie the benefits of spaced study and spaced retrieval practice.