Unique lncRNA signatures mark the major T-ALL genetic subgroups

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SOX11 is a lineage-survival oncogene in neuroblastoma

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SOX11 is a lineage-survival oncogene in neuroblastoma

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The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity

ALK is an important druggable target in ALK mutant neuroblastoma (NB). In this study, we sought novel vulnerable nodes downstream of ALK for combinatorial therapy. First, we identified a 79-gene signature that recapitulates the transcriptional response upon ALK inhibition based on transcriptome profiling of ALK wild type, ALKF1174L or ALKR1275Q mutant and ALK amplified NB cell lines following ALK inhibition using NVP-TAE684, LDK-378, X-396 and Crizotinib. This signature was validated in primary tumor samples and in the SK-N-AS cell line with regulated expression of ALK wild type, ALKF1174L and ALKR1275Q constructs. The majority of the mutant ALK dependent downstream signaling components were implicated in MAPK/ERK, PI3K/AKT/mTOR, MYC/MYCN and neuronal differentiation signaling. Bioinformatic analysis using the iRegulon Cytoscape plugin (http://ift.tt/1nlxfL5) resulted in the identification of the transcriptional repressor HBP1 as a hub gene, acting downstream of ALK. HPB1 is a known negative regulator of MYC/MYCN activity. Using MYCN and miR-17-92 inducible SHEP model systems, we established a MYCN/miR-17-92/HBP1 positive feedback regulatory loop in which MYCN represses the negative control of HBP1 through upregulation of miR-17-92 which targets the HBP1 3'UTR. Next, we showed that stable HBP1 overexpression inhibits growth and induces apoptosis of NB cells. Finally, we explored the effects of the green tea compound epigallocatechin gallate (EGCG) on HBP1 upregulation in NB cells. EGCG treatment induced HBP1 expression and had a strong negative effect on cell growth and survival. EGCG/ALK inhibitor combination treatment in a panel of cell lines showed clear additive effects. In conclusion, we identified HBP1 as a novel important ALK downregulated gene controlling MYCN activity, further stressing the important interconnection between oncogenic MYCN and ALK signaling. EGCG upregulates HBP1 levels and is a strong candidate for further in vivo testing for additive or synergistic effects with ALK inhibitors or MYCN targeting compounds such as JQ1.

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Phf6 plays a role in hematopoiesis and thymopoiesis in zebrafish

T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of thymocytes and affects both children and adults. In T-ALL, multiple genetic lesions in oncogenes and tumor suppressor genes cooperatively contribute to leukemogenesis. Recently, our research group identified inactivating mutations and deletions in the PHF6 gene in 16% of pediatric and 38% of adult T-ALL patients. Although these frequencies suggest an important role for PHF6 as a tumor suppressor in T-ALL, the role of PHF6 in normal and malignant T-cell development remains largely unknown. Whole mount in situ hybridization (WISH) revealed phf6 expression in developing zebrafish in hematopoietic regions and in the thymus. Upon morpholino-mediated knockdown of phf6, WISH experiments demonstrated a normal onset of primitive hematopoiesis at 15 somites, while increased expression of lmo2, a marker for primitive hematopoiesis and erythropoiesis at 24hpf (hours post fertilization) can be observed. Moreover, also c-myb expression, a marker for definitive hematopoiesis, is increased in the caudal hematopoietic tissue at 36hpf after phf6 knockdown. Rag1 and rag2 are useful markers for following the development of lymphoid tissues since they are expressed together exclusively in immature lymphocytes. Interestingly, a significant reduction in thymus development and size could be observed in phf6 morphants at 5dpf (days post fertilization) using the transgenic zebrafish line tg(Rag2:GFP). In line with these results, strongly reduced rag1 expression was evident upon performing WISH on 5dpf phf6 knockdown embryos, as compared to control embryos. All together, our data provide strong evidence for an important role of phf6 in primitive hematopoiesis and thymopoiesis. Further studies will include phf6 knockout zebrafish to assess long-term effects and susceptibility to T-ALL formation in vivo.

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Vitamin D Deficiency Is Associated with Rapid Decline in Exercise Capacity in Male Patients with Chronic Obstructive Pulmonary Disease

Background: Vitamin D is suggested to play a role in airway and systemic inflammation in chronic obstructive pulmonary disease (COPD). Low serum 25-hydroxyvitamin D (25-OHD) levels have been suggested to be associated with lower lung function and poorer exercise capacity in COPD. Objectives: The main purpose of this study was to investigate the effects of vitamin D deficiency on the change in exercise capacity in male COPD patients. Methods: A total of 156 male subjects were selected from the Korean Obstructive Lung Disease cohort. Vitamin D deficiency was subdivided into three subgroups: mild, moderate, and severe deficiency groups. Rapid decline was defined as an annual rate of change in exercise capacity ≥17 m. Exercise capacity was assessed by 6-minute walk distance (6MWD). Results: Significant differences were observed in the serum levels of 25-OHD, the number of patients with vitamin D sufficiency, and moderate-to-severe deficiency between rapid decliners (n = 40) and non-rapid decliners (n = 116). No differences were found between the groups for age, smoking status, lung function, and 6MWD. Multivariate analysis showed that vitamin D deficiency was independently related to rapid decline in exercise capacity (p = 0.028). A statistically significant difference was observed among the subgroups of vitamin D deficiency in terms of the change in exercise capacity (p Conclusion: This study shows that vitamin D deficiency is associated with rapid decline in exercise capacity in male patients with COPD.
Respiration

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Establishing a national paediatric radiology global outreach group recent developments in the British Society of Paediatric Radiology

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