Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy

Ethical and moral dilemmas associated with strategic relationships between business-to-business buyers and sellers

While ethical and moral issues have been widely considered in the general areas of marketing and sales, similar attention has not been given to the impact of strategic account management (SAM) approaches to handling the relationships between suppliers and very large customers. SAM approaches have been widely adopted by suppliers as a mechanism for managing relationships and partnerships with dominant customers - characterized by high levels of buyer - seller inter-dependence and forms of collaborative partnership. Observation suggests that the perceived moral intensity of these relationships is commonly low, notwithstanding the underlying principles of benefiting the few ( large, strategic customers) at the expense of the many ( smaller customers and other stakeholders), and the magnitude of the consequences of concessions made to large customers, even though some such consequences may be unintended. Dilemmas exist also for executives implementing strategic account relationships regarding such issues as information sharing, trust, and hidden incentives for unethical behaviour. We propose the need for greater transparency and senior management questioning of the ethical and moral issues implicit in strategic account management

How Corporate Social Performance Is Institutionalised Within the Governance Structure

Since Ackerman in Corporate social responsiveness, the modern dilemma (1973), pleaded for the institutionalisation of corporate social performance (CSP) in business processes, researchers have focused on the role of strategy in CSP. This article demonstrates that CSP is institutionalised within the governance structure. We will attempt to make this clear by means of a description of the Dutch system of corporate governance. Under certain circumstances Dutch companies are already bound to CSP due to prevailing legislation. A governance perspective shows that CSP is institutionalised within a company’s governance structure. “Processes of responsivenessâ€\x9D, since long regarded as a starting point of CSP-analysis, appear to be decision-making processes. Within these processes the expectations of the stakeholders can be institutionalised, trust can be built and interests can be incorporated. This makes CSP context-dependent. However, it is possible to analyse companies by comparing the companies’ individual governance structures. The article concludes that CSP-analysis can fruitfully extend into analysing in the role of the stakeholders in the influence-pathways that are incorporated within the governance structure. Copyright Springer Science+Business Media B.V. 2007corporate governance, corporate social performance, stakeholder influence,

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies

Wiedemann–Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients