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To cite this version:Fransiska Malfait, Delfien Syx, Philip Vlummens, Sofie Symoens, Sheela Nampoothiri, et al.. Musculocontractural Ehlers-Danlos syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene.. Human Mutation, Wiley, 2010, 31 (11) show that both conditions form a phenotypic continuum. Our findings confirm that the EDSvariant associated with CHST14 mutations (Miyake, et al., 2010) forms a clinical spectrum, which we propose to coin as "musculo-contractural EDS" and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5 and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in 2 probands, whereas 9 probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastro-intestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor beta (TGFβ) signaling. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs*27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ signaling. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

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Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid metabolism, with the upregulation of several ceramides and downregulation of sphingomyelin. This imbalance suggests an increase in sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. We confirmed the upregulation of acid sphingomyelinase (ASM) in primary MM cells. Furthermore, we observed an increase in ASM expression in MM cell lines treated with melphalan or bortezomib, as well as in their exosomes. Exosomes high in ASM content were able to transfer the drug-resistant phenotype to chemosensitive cells, hereby suggesting a tumor-protective role for ASM. Finally, inhibition of ASM by amitriptyline improved drug sensitivity in MM cell lines and primary MM cells. In summary, this study is the first to analyze differences in plasma lipid composition of MM patients and match the observed differences to an upregulation of ASM. Moreover, we demonstrate that amitriptyline is able to inhibit ASM and increase sensitivity to anti-myeloma drugs. This study, therefore, provides a rational to include ASM-targeting-drugs in combination strategies in myeloma patients.

Summary Treatment benefit in multiple myeloma (MM) patients with high‐risk cytogenetics remains suboptimal. The phase 3 ICARIA‐MM trial (NCT02990338) showed that isatuximab plus pomalidomide–dexamethasone prolongs median progression‐free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA‐MM compared the benefit of isatuximab in high‐risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard‐risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA‐MM, 307 patients received isatuximab–pomalidomide–dexamethasone (n = 154) or pomalidomide–dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28‐day cycle, and every other week thereafter. Standard pomalidomide–dexamethasone doses were given. Isatuximab–pomalidomide–dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33–1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high‐risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28–0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high‐risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment‐related mortality. Isatuximab–pomalidomide–dexamethasone provides a consistent benefit over pomalidomide–dexamethasone treatment in RRMM patients regardless of cytogenetic risk.