Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1, and TGFBR1. Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis.
Generalized pustular psoriasis (GPP) is a rare, chronic, neutrophilic inflammatory skin disease characterized by episodes of widespread eruption of sterile, macroscopic pustules that can be accompanied by systemic inflammation and symptoms. A systematic literature review and narrative synthesis were conducted to determine the impact of GPP on patients' health-related quality of life (HRQoL) and patient-reported severity of symptoms and to compare its impact to patients with plaque psoriasis (plaque PsO). Searches were undertaken in Embase, MEDLINE and the Cochrane Library from 1 January 2002 to 15 September 2022. Screening was carried out by two reviewers independently. Outcome measures included generic (e.g. EQ-5D, SF-36) and dermatology-specific (e.g. DLQI) clinical outcome assessments, and other relevant patient-reported outcome measures (PROMs) (e.g. severity of pain measured by a numerical rating scale). Overall, 20 studies were found to be eligible for inclusion, of which seven also had data for plaque PsO. The DLQI was the most frequently reported outcome measure (16 out of 20 studies). When reported, mean DLQI (SD) scores varied from 5.7 (1.2) to 15.8 (9.6) across the studies, indicating a moderate to very large effect on HRQoL; the wide range of scores and large SDs were explained by the small population sizes (n ≤ 12 for all studies except two). Similar ranges and large SDs were also observed for other measures within individual studies. However, in general, people with GPP reported a greater impact of their skin condition on HRQoL, when compared to people with plaque PsO (i.e. higher DLQI scores) and higher severity for itch, pain and fatigue. This systematic review highlighted the need for studies with a larger population size, a better understanding of the impact of cutaneous and extracutaneous symptoms and comorbidities on HRQoL during and between GPP flares, and outcome measures specifically tailored to the unique symptoms and the natural course/history of GPP.
Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.