ABSTRACT. Leukemia stem cells (LSCs) are regarded as the origin of leukemia and its recurrence. Side population (SP) cells possess some intrinsic stem cell properties and contain numerous LSCs. In this study, we examined the prognostic significance of cluster differentiation 47 (CD47) and identified the appropriate target for eliminating LSCs. We determined the percentage of SP cells in a THP-1 cell population and analyzed CD47 expression in different cell subsets. We then explored whether CD47 affected the phagocytic ability of macrophages to LSCs in vitro. Finally, the effect of anti-CD47 monoclonal antibodies, alone or combination with cytarabine, against leukemic cells was evaluated in vitro and in vivo to identify the optimal targets for the treatment of leukemia. We observed an SP sub-fraction at low frequency (1.81 ± 0.99%), which was a likely candidate for LSC enrichment. CD47 was more highly expressed on THP-1 LSCs (P < 0.05) and was an independent predictor of survival and refractory disease in THP-1-engrafted mice. Furthermore, the anti-CD47 monoclonal antibody stimulated preferential phagocytosis of LSCs by macrophages in vitro. Finally, single or combination treatment of THP-1 LSC-engrafted mice 5631 Combination therapy eliminates leukemic cells ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 5630-5641 (2015) with cytarabine and anti-CD47 antibody resulted in targeting of LSCs and depletion of leukemia cells. These findings suggest that CD47 is an antibody target in LSCs and combination treatment with cytarabine and anti-CD47 monoclonal antibody represents an attractive option for the therapeutic targeting of acute monocytic leukemia.

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Background. This study aimed to assess the mechanism through which Wnt/ beta-catenin signaling pathway, and StarD7, prometes testosterone synthesis, and to explore a new pathway for the regulation of testosterone synthesis. Animals and Methods. Leydig cells were isolated from male Sprague-Dawley rats divided into four groups and treated with Annexin 5 in concentration of 0, 0.1, 1 and 10 nmol/L. Testosterone secretion, expression of StarD7, StarD7 mRNA, β-catenin and changes of β-catenin localization in Leydig cells of testis of rats were tested in the four groups. Results. mRNA and protein levels of StarD7 and β-catenin increased significantly, upon stimulation with 1 nmol/L annexin 5. Accumulation of β-catenin inside the cells and the nucleus, was observed by immunofluorescence staining, in cells treated with annexin 5. These findings indicate a possible role of StarD7 and β-catenin in the process of annexin5-mediated stimulation of testosterone synthesis. Conclusions. Wnt/β-catenin signaling pathway and StarD7 are involved in the process of annexin5 stimulation of testosterone synthesis. Activation of Wnt/ β-catenin signaling pathway by Annexin5, and increase in StarD7 expression lead to elevated expression of key regulatory enzymes in testosterone synthesis, thus promoting testosterone synthesis.