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•An inflammatory BMM with elevated levels of PGE2 accelerates the progression of PGE2-sensitive AML.•A specific subset of patients with AML may benefit from combination treatment with COX2 inhibition and standard chemotherapy.

Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEVs released by BMM-derived mesenchymal stromal cells (MSCs). PLEKHM1-deficient MSCs and their sEVs carry increased amounts of syntenin and syndecan-1, resulting in a more immature B-cell phenotype and an increased number/function of leukemia-initiating cells (LICs) via focal adhesion kinase and AKT signaling in B-ALL cells. Ex vivo pretreatment of LICs with sEVs derived from PLEKHM1-deficient MSCs led to a strong trend toward acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL cell–derived tumor necrosis factor α or interleukin-1β condition murine and human MSCs in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSCs, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSCs. In summary, our data reveal an important role of BMM-derived sEVs for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared with BCR-ABL1− B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.

•The PLEKHM1-associated endolysosomal system in MSCs affects BCR-ABL1+B-ALL progression via release of extracellular vesicles.•B-ALL–derived inflammatory cytokines perpetuate this circuit in MSCs, modify vesicular cargo, and promote B-ALL cell signaling and survival.

Calcium, the most abundant mineral in the body, is a key component of bones and is released by bone remodelling. Calcium ions play a role in the localisation, engraftment and the adhesion of normal haematopoietic stem cells (HSC) to extracellular matrix (ECM) proteins in the bone marrow microenvironment (BMM) via the calcium sensing receptor (CaSR), thereby maintaining normal haematopoiesis. However, the role of this heterotrimeric G-protein-coupled receptor and its associated pathways in the local BMM for the development of leukaemia is poorly understood.

ABSTRACTFlow cytometry (FC) is a straightforward, highly specific and sensitive procedure, which provides objective and quantitative recording of fluorescent signals from individual cells. FC has been used widely in the area of aquaculture research due mainly to the development of monoclonal antibodies (mabs). Phagocyte activity of head–kidney macrophages of several fish species, antibody production against specific antigens or detection of viruses inside immune cells are some of the several possible analysis approached by this assay. The aim of this work is to analyse and to compare kinetics of IgM-positive cells in the gill and spleen of sea bream juveniles after bath immunization against Photobacterium damselaesubsp. piscicida(Phdp) using a direct staining method. Fish were immunized with three different inactivated vaccines prepared with 94/99 antigen and a commercial vaccine was used as a positive control. The effect on IgM-positive cells post-vaccination was compared among groups. Results show that the direct staining method with mabs is an effective and repeatable method for staining sea bream IgM-positive cells.

Hafnia alveiis a Gram negative bacterium that belongs to the family Enterobacteriaceae. It is part of the intestinal flora of humans and animals, moreover it has been described from natural environments and foodstuffs. In human medicine is considered an opportunistic bacterium that causes different infections associated to underlying illnesses or predisposing factors as immunocompromised patients. The knowledge and literature about this bacterium in veterinary medicine is scarce, highlighting its importance in gastropods and bees, and it has also been described in poultry, mares, fish and ruminants producing various clinicopathologic signs.

In this work, we evaluated the effect of the probiotic Enterococcus gallinarumL-1 on the cellular immune system of four different fish species of great interest in aquaculture such as gilthead sea bream (Sparus aurata), European sea bass (Dicentrarchus labrax), meagre (Argyrosomus regius) and red porgy (Pagrus pagrus). Phagocytic activity, respiratory burst and peroxidase content of leucocytes were observed 30 minutes after incubation with the probiotic E. gallinarumstrain L-1, alive or inactivated with heat shock or ultraviolet (UV) light at different concentrations of 107, 108and 109cfu mL−1(final concentration 106, 107and 108cfu mL−1). E. gallinarumproduced dose-dependent increments in respiratory burst in red porgy, sea bream and sea bass leucocytes. About 106and 107cfu mL−1of live and inactivated bacteria with no stimulation of the respiratory burst activity of sea bream and red porgy head kidney leucocytes was shown. The highest values of peroxidase content were observed in red porgy cells with stimulation indexes higher than 1 in each treatment. Statistical analysis revealed that differences were only significant in sea bream where UV light-inactivated bacteria denote statistically significant differences (P< 0.05) with respect to other treatments. Highest values of phagocytic activity were obtained in sea bream leucocytes incubated with live bacteria (26% ± 1.88), where significant differences (P< 0.05) with other species were detected. Our results suggest that the in vitroassays may be useful in optimising their effective dose and viability for the immunomodulatory effects of probiotic bacteria, although in vivostudies are necessary to confirm the immunomodulatory effect of this strain.