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Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed–Sternberg cells (RS-cells) has evolved drastically in the last decades. More recently, a better characterization of the signaling pathways and the cellular interactions at play have paved the way for new targeted therapy in the hopes of improving outcomes. However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. Here, we discuss the past, present, and future of cHL, and review in detail the more recent discoveries pertaining to genetic instability, anti-apoptotic signaling pathways, the tumoral microenvironment, and host-immune system evasion in cHL.

Classic Hodgkin’s lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15–20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients’ response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively.

Androgen-deprivation therapy (ADT) has become a standard of care in the management of advanced prostate cancer or as an adjunct therapy. However, ADT is associated with a well-known deleterious effect on bone health, resulting in a decrease in bone-mass density (BMD) and increased risk for fracture. With the longer life expectancy of prostate cancer patients, improvement of the quality of life has become increasingly important. Therefore, adequate screening, prevention and treatment of BMD loss is paramount. Zoledronic acid and denosumab have shown promising results in recent studies, which has led to the Food and Drug Administration approval of these treatment options in various settings throughout the course of the disease, including the prevention of ADT-associated bone loss. This review focuses on the various parameters that impact BMD loss in men initiating ADT, on the specific effect of ADT on bone health and on various lifestyle modifications and treatment options such as bisphosphonates, osteoclast-targeted therapy and selective estrogen-receptor modulators that have shown promising results in recent studies.

A 76-year-old man originally from Barbados was admitted to hospital after experiencing one month of progressive generalized weakness that culminated in his inability to carry out independent activities of daily living. The patient's medical history included hypertension, type 2 diabetes, previous smoking (20 pack-years) and diabetic nephropathy that resulted in a kidney transplant six years earlier. After transplantation surgery, the patient had experienced stage 5 chronic renal insufficiency as a result of progressive allograft dysfunction. The patient was taking an immune suppression regimen consisting of extended release tacrolimus (25 mg/d), mycophenolate mofetil (720 mg, twice daily) and prednisone (5 mg/d). Early recognition and prompt initiation of directed antimicrobial therapy can substantially affect the outcome of pet-transmitted zoonotic infections in patients with compromised immune systems. As shown in our patient's case, some zoonotic infections can disseminate and have a life-threatening course.

The treatment of patients with PNH has been revolutionized by terminal complement C5 inhibitors, which control intravascular hemolysis and thrombosis, reduce morbidity and mortality, and improve life expectancy to that approaching people without PNH. In recent years, approval of proximal inhibitors provides clinicians and patients with additional treatment options such that patients who have residual anemia, ongoing symptoms affecting quality of life, or are intolerant to terminal C5 inhibition now have options to optimize treatment. Here, we provide five questions to guide clinicians involved in the care of patients with PNH in assessing treatment response on terminal inhibitors and identifying patients who might benefit from therapy adjustments. We also provide insights into additional treatment options.

Wnt/β-catenin signaling elicits context-dependent transcription switches that determine normal development and oncogenesis. These are mediated by the Wnt enhanceosome, a multiprotein complex binding to the Pygo chromatin reader and acting through TCF/LEF-responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing β-catenin via the Legless/BCL9 adaptor. We used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses. BioID proximity labeling revealed that BCL9 and B9L, like PYGO2, are constitutive components of the Wnt enhanceosome. Wnt-dependent docking of β-catenin to the enhanceosome apparently causes a rearrangement that apposes the BCL9/B9L C-terminus to TCF. This C-terminus binds to the Groucho/TLE co-repressor, and also to the Chip/LDB1-SSDP enhanceosome core complex via an evolutionary conserved element. An unexpected link between BCL9/B9L, PYGO2 and nuclear co-receptor complexes suggests that these β-catenin co-factors may coordinate Wnt and nuclear hormone responses. In every animal, different cells must be able to communicate with each other to make sure that the body is correctly formed and maintained. Animal cells have many ways of communicating, but one important and well-studied mechanism involves a signaling molecule called Wnt that is released by some cells and received by others. The Wnt molecule and its effects are similar in all animals, and over-active Wnt signaling in humans contributes to a number of diseases including various cancers. The Wnt signal is carried from the surface of the receiving cell to the DNA in its nucleus via a protein called β-catenin. The β-catenin protein then helps to switch on a large number of genes. However, to do this β-catenin must interact with an assembly of other proteins collectively called the Wnt enhanceosome. There are still many unknowns about how exactly β-catenin cooperates with the enhanceosome. Now, van Tienen et al. investigated one component of the Wnt/β-catenin pathway called BCL9/B9L: a large protein that contains a number of flexible regions. First, a biochemical technique called BioID was used with human embryonic kidney cells to determine the proteins that BCL9/B9L encounters during a 12-hour period. This technique can detect when two proteins come close together, even if the interaction is weak or does not last very long. The BioID experiments showed that BCL9/B9L is close to two proteins in the Wnt enhanceosome in addition to β-catenin, and other techniques were used to confirm that one of these proteins contacts BCL9/B9L directly. The experiments also showed that BCL9/B9L acted as a tether to bring β-catenin close to the protein within the enhanceosome that binds to the DNA. Importantly, BCL9/B9L interacted with the enhanceosome both in the presence and absence of Wnt, indicating that the assembly is ready to switch genes on as soon as β-catenin reaches the DNA. Next, van Tienen et al. confirmed that the parts of BCL9/B9L that bind to the enhanceosome are important for its activity by using a gene-editing technology called CRISPR/Cas9 to essentially delete them both in the human cells and in fruit flies. Unexpectedly, the BioID experiments also revealed that BCL9/B9L binds to proteins that transmit signals from molecules other than Wnt, in particular from hormones such as estrogen and androgen. Future experiments could explore if, and how, BCL9/B9L integrates these signals from hormones with the signal from Wnt. A better understanding of this process might have important implications for the treatment of certain cancers, such as breast and prostate cancers that can be driven by over-active hormone signals.

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1–4 from the 5′ end of the Trk fused Gene (TFG) fused to the 3′ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis. Papillary thyroid cancer (PTC) is one of the most common type of endocrine malignancy. Here, the authors use proteogenomic approaches to analyse the primary tumour and lymph node metastases from a PTC patient and report an oncogenic RET fusion, and potential druggable targets from the ubiquitin signaling machinery for treating human PTCs.

Wnt/β-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, β-catenin is targeted continuously for proteasomal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation by Dishevelled, which recruits Axin to the plasma membrane and assembles it into a signalosome. This key event during Wnt signal transduction depends on dynamic head-to-tail polymerization by the DIX domain of Dishevelled. Here, we use rescue assays in Drosophila tissues and functional assays in human cells to show that polymerization-blocking mutations in the DIX domain of Axin disable its effector function in down-regulating Armadillo/β-catenin and its response to Dishevelled during Wnt signaling. Intriguingly, NMR spectroscopy revealed that the purified DIX domains of the two proteins interact with each other directly through their polymerization interfaces, whereby the same residues mediate both homo- and heterotypic interactions. This result implies that Dishevelled has the potential to act as a \"natural\" dominant-negative, binding to the polymerization interface of Axin's DIX domain to interfere with its self-assembly, thereby blocking its effector function.

The Chip/LIM-domain binding protein (LDB)–single-stranded DNA-binding protein (SSDP) (ChiLS) complex controls numerous cell-fate decisions in animal cells, by mediating transcription of developmental control genes via remote enhancers. ChiLS is recruited to these enhancers by lineage-specific LIM-domain proteins that bind to its Chip/LDB subunit. ChiLS recently emerged as the core module of the Wnt enhanceosome, a multiprotein complex that primes developmental control genes for timely Wnt responses. ChiLS binds to NPFxD motifs within Pygopus (Pygo) and the Osa/ARID1A subunit of the BAF chromatin remodeling complex, which could synergize with LIM proteins in tethering ChiLS to enhancers. Chip/LDB and SSDP both contain N-terminal dimerization domains that constitute the bulk of their structured cores. Here, we report the crystal structures of these dimerization domains, in part aided by DARPin chaperones. We conducted systematic surface scanning by structure-designed mutations, followed by in vitro and in vivo binding assays, to determine conserved surface residues required for binding between Chip/LDB, SSDP, and Pygo-NPFxD. Based on this, and on the 4:2 (SSDP-Chip/LDB) stoichiometry of ChiLS, we derive a highly constrained structural model for this complex, which adopts a rotationally symmetrical SSDP₂-LDB₂-SSDP₂ architecture. Integrity of ChiLS is essential for Pygo binding, and our mutational analysis places the NPFxD pockets on either side of the Chip/LDB dimer, each flanked by an SSDP dimer. The symmetry and multivalency of ChiLS underpin its function as an enhancer module integrating Wnt signals with lineage-specific factors to operate context-dependent transcriptional switches that are pivotal for normal development and cancer.

TCF/LEF factors are ancient context-dependent enhancer-binding proteins that are activated by β-catenin following Wnt signaling. They control embryonic development and adult stem cell compartments, and their dysregulation often causes cancer. β-catenin-dependent transcription relies on the NPF motif of Pygo proteins. Here, we use a proteomics approach to discover the Chip/LDB-SSDP (ChiLS) complex as the ligand specifically binding to NPF. ChiLS also recognizes NPF motifs in other nuclear factors including Runt/RUNX2 and Drosophila ARID1, and binds to Groucho/TLE. Studies of Wnt-responsive dTCF enhancers in the Drosophila embryonic midgut indicate how these factors interact to form the Wnt enhanceosome, primed for Wnt responses by Pygo. Together with previous evidence, our study indicates that ChiLS confers context-dependence on TCF/LEF by integrating multiple inputs from lineage and signal-responsive factors, including enhanceosome switch-off by Notch. Its pivotal function in embryos and stem cells explain why its integrity is crucial in the avoidance of cancer. In animals, cells have to be able to communicate with neighboring cells in order to generate and maintain the different tissues and organs. One ancient method of cell communication that is used in all animals is the Wnt signaling pathway. In this pathway, a cell secretes a protein called Wnt, which binds to a Wnt receptor present on the surface of another cell. This triggers a cascade of signals inside the second cell that leads to the activation of proteins called TCF factors. These proteins bind to regions of DNA called enhancers to trigger the expression of particular genes that control the development of the animal. Hyperactive Wnt signaling in humans can result in cancer, so Wnt signaling is tightly controlled to avoid this. One of the proteins that regulates Wnt signaling is called Groucho and it interacts with TCF to prevent it from activating genes in the absence of a Wnt signal. However, when Wnt is present, a protein called Pygo overcomes this repression by Groucho to activate TCF, but it is not clear how this works. Fiedler, Graeb, Mieszczanek et al. discovered that Pygo directly binds to a protein complex called Chip/LDB-SSDP (or ChiLS for short). ChiLS is able to associate with TCF enhancers through its association with Groucho. Fiedler, Graeb, Mieszczanek et al. observed that ChiLS can also interact with a number of other proteins that control body formation. This enables ChiLS to integrate multiple signals that regulate the activity of TCF factors. Fiedler, Graeb, Mieszczanek et al. named this complex the ‘Wnt enhanceosome’ because it serves to activate the expression of genes in response to Wnt signaling. Fiedler, Graeb, Mieszczanek et al. analyzed the role of the Wnt enhanceosome during the development of the fly wing and the embryo's midgut. Many genes that are required to form these organs were switched on by the Wnt enhanceosome. This study shows that ChiLS and Pygo are core components of a large complex of proteins that regulate animal development. The next challenge is to study how the components of this complex work together to regulate the enhancers in response to different signals.