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New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM., (© 2017 John Wiley & Sons Ltd.)

I Sir: i The 3rd session of the bone marrow (BM) workshop of the 19th meeting of the European Association for Haematopathology (EAHP)/Society of Hematopathology (SH) in Edinburgh in 2018 was dedicated to T-cell and natural killer (NK)/T-cell lymphomas/lymphoproliferations. In this article we discuss cases submitted to the 3rd session of the EAHP/SH BM workshop and focus on diagnostic challenges, including the difficulties in clarifying borders between overlapping primary BM T-cell and NK/T-cell lymphoproliferations, and the limitations of applying existing diagnostic criteria related to nodal-type T-cell lymphomas or extranodal NK/T-cell (ENKT) lymphoproliferations to rare cases of isolated involvement or initial presentation in the BM. GLO:EW1/01jul20:his14093-fig-0003.jpg PHOTO (COLOR): 3 Angioimmunoblastic T-cell lymphoma with bone marrow (BM) involvement that was obscured by a dense polytypic plasmacytic infiltrate, and a case of primary BM involvement by peripheral T-cell lymphoma expressing T follicular helper cell (TFH) markers. A,B, Bone marrow (BM) examination of case no. 21/217 showed dense infiltration by two topographically and morphologically distinct lymphoid infiltrates: confluent nodules of small lymphoid cells [A, haematoxylin and eosin (H&E)], and (B) many large bizarre atypical lymphoid cells in a fibrotic background of small lymphoid cells and histiocytes (B, H&E). [Extracted from the article]