Search

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.Leukemia advance online publication, 30 June 2017; doi:10.1038/leu.2017.183.

In the period 2013–2014 a survey was carried out on the helminthic fauna of 60 wild canids, 57 red foxes (Vulpes vulpes) and three wolves (Canis lupus italicus), collected in the Emilia-Romagna region, Italy. The study focused mainly on the gastrointestinal and hepatic helminths. Parasites were recovered in 91.2% of the red foxes and in all the wolves examined. Multiple infections were found in the majority of the animals (71.9% of the foxes and 100% of the wolves). In total, 14 intestinal helminth species were identified, two trematodes (Alaria alata, Brachylaima spp.), seven cestodes (Mesocestoides spp., Taenia crassiceps, Taenia pisiformis, Taenia polyacantha, Dipylidium caninum, Taenia ovis, Taenia hydatigena) and five nematodes (Uncinaria stenocephala, Toxocara canis, Trichuris vulpis, Pterigodermatites affinis, Ancylostoma caninum). The heartworm Dirofilaria immitis was also recovered in two foxes. No Echinococcus spp. were found. Our study shows that foxes are reservoir hosts of zoonotic parasites, including A. alata, a rare digenean trematode in the Italian paeninsula. Results are compared with those of other surveys on helminths of wild canids carried out in Italy and other European countries.