Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/β-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated β-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)γc(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration.

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Abstract. Understanding the role of microenvironment in cancer growth and metastasis is a key issue for cancer research. Here, we study the effect of osmotic pressure on the functional properties of primary and metastatic melanoma cell lines. In particular, we experimentally quantify individual cell motility and transmigration capability. We then perform a circular scratch assay to study how a cancer cell front invades an empty space. Our results show that primary melanoma cells are sensitive to a low osmotic pressure, while metastatic cells are less. To better understand the experimental results, we introduce and study a continuous model for the dynamics of a cell layer and a stochastic discrete model for cell proliferation and diffusion. The two models capture essential features of the experimental results and allow to make predictions for a wide range of experimentally measurable parameters. PACS. PACS-key discribing text of that key -PACS-key discribing text of that key

Fluoxetine (FLX) is one of the main antidepressants used worldwide. After human use FLX enters the aquatic ecosystems, where it has commonly detected in the high ng/L concentration range. Several investigations have shown that exposure to different concentrations of FLX caused different adverse effects towards a number of aquatic species. However, the information on the onset and the relationship between molecular and behavioral FLX-induced effects remains scant. The aim of this study was to assess the effects induced by two FLX concentrations, namely 50 ng/L and 500 ng/L, on swimming activity of zebrafish (Danio rerio) larvae at 96 hours post fertilization (hpf) and to investigate if such behavioral effects were related to modulation of the expression of oxidative stressrelated (sod1, sod2, cat, gpxa and gst), stress and anxiety-related (oxtl, prl2, npy and ucn3l) genes, and genes encoding for the transporters of the main neurotransmitters (slc6a3, slc6a4a, slc6a4b, slc6a11). Fluoxetine exposure altered the swimming behavior of larvae, as shown by the reduction of the distance traveled by treated larvae in response to an external stimulus. Such behavioral change was related, at molecular level, to an enhanced expression of sod1, cat and gpxa, suggesting an overproduction of pro-oxidant molecules. In addition, FLX modulated the expression of oxtl, slc6a4a, slc6a4b and slc6a11, suggesting its capability to affect anxiety-and neurotransmitter-related genes.

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