The optimal treatment sequence for high risk (HR) myeloma has not been defined and many experts recommend various intensifications for this subpopulation, including quadruplets, consolidation, tandem CORRESPONDENCE E35

ß-thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (i.e. using hepcidin activators like Tmprss6-antisense oligonucleotides (ASO)) or increase erythropoiesis (by erythropoietin (EPO) administration or by modulating the ability of transferrin receptor 2 (Tfr2) to control red blood cell (RBC) synthesis). Targeting Tmprss6 mRNA by Tmprss6-ASO was proven to be effective in improving the IE and splenomegaly by inducing iron restriction. However we postulated that combinatorial strategies might be superior to single therapies. Here we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by ß-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single allele deletion alone, respectively, exacerbated or did not improve the splenomegaly in ß-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve the splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, combination of Tmprss6-ASO+EPO or Tmprss6-ASO+Tfr2 single allele deletion showed significantly higher hemoglobin levels as well as reduction of splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating the IE and anemia in ß-thalassemia and could provide guidance to translate some of these approaches into viable therapies.

Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a congenital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON - devoid cells, and blunt the insulin-mediated glucose uptake of SELENON - devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations.