Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma.

The expression of BCL6 in B-cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions, or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase that is involved in the degradation of BCL6, and it is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of patients with Burkitt lymphoma (BL). FBXO11 mutations impaired BCL6 degradation, and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of 1 or 2 copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B-cell lymphoma onset, providing experimental evidence that FBXO11 is a haploinsufficient oncosuppressor in B-cell lymphoma. In wild-type and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degraders or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL, we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches, such as BCL6 degraders and direct MYC inhibition, could be exploited as a targeted therapy for BL.

Assessing demoralization in medically ill patients: Factor structure of the Italian version of the demoralization scale and development of short versions with the item response theory framework.

OBJECTIVE: Demoralization has been mostly investigated in oncology but is also relevant for patients with other physical illnesses. Our aims were to investigate the psychometric properties of the 24-item Italian version of the Demoralization Scale (DS-24) among medically ill inpatients, and to develop shorter versions for screening. METHODS: Four-hundred and seventy-three participants were recruited from medical wards of the University Hospital of Ferrara. Patients were assessed using the Diagnostic Criteria for Psychosomatic Research-Demoralization module (DCPR/D), Demoralization Scale (DS-24), Patient Health Questionnaire-9 (PHQ-9), Brief-Symptom Inventory-18, Anxiety subscale (BSI-Anx) and EuroQol Group (EQ-5D). Confirmatory factor analyses of previous structures and exploratory factor analyses were conducted using an Item Response Theory approach, including a bifactor model. RESULTS: According to DCPR/D criteria, the prevalence of demoralization was 40%. Confirmatory analyses revealed that none out of seven factor structures from oncology studies adequately fitted data from hospital inpatients. Exploratory Item Factor Analysis uncovered a four-factor model comprising Disheartenment, Dysphoria, Sense of Failure, Loss of Meaning and Purpose, or a bifactor model, comprising similar factors with the addition of a general factor accounting for 45% of the variance. Moreover, we developed 13 and 6-item versions of the DS, both retaining high correlation with DS-24 scores (r = 0.98 and r = 0.95, respectively) and concordance with DCPR/D criteria (AUC-ROC 0.82 and 0.81). CONCLUSION: The DS factor structure differs between general hospital and cancer patients. Differences may depend on intrinsic disease features and cultural-geographic factors. The short versions of the DS-24 may aid clinicians in identifying demoralized patients in hospital settings.

Beyond pain: can antidepressants improve depressive symptoms and quality of life in patients with neuropathic pain? A systematic review and meta-analysis.

Neuropathic pain can be a predictor of severe emotional distress, up to full-blown depressive states. In these patients, it is important to move beyond the sole treatment of pain, to recognize depressive symptoms, and to ultimately improve the quality of life. We systematically searched for published and unpublished clinical trials assessing the efficacy and tolerability of antidepressants vs placebo on depression, anxiety and quality of life in patients with neuropathic pain, and pooled data in a meta-analysis. A total of 37 studies fulfilled eligibility criteria and 32 provided data for meta-analysis. Antidepressants were more effective than placebo in improving depressive symptoms (standardized mean difference -0.11; 95% confidence interval -0.20 to -0.02), although the magnitude of effect was small, with a number needed to treat of 24. No significant difference emerged between antidepressants and placebo in reducing anxiety. Quality of life seemed improved in patients on antidepressants, as did pain. Acceptability and tolerability were higher in patients on placebo. To the best of our knowledge, this is the first meta-analysis specifically focusing on the effect of antidepressants on psychiatric symptoms and quality of life in patients with neuropathic pain. Our findings suggest that despite their potential benefit in patients with neuropathic pain, antidepressants should be prescribed with particular care because they might be less tolerable in such a fragile population. However, our findings warrant further research to explore how a correct use of antidepressants can help patients to cope with the consequences of neuropathic pain on their psychosocial health and quality of life.

Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.

In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-ß. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.