Macrophages exhibit phenotypic heterogeneity under both physiological and pathological conditions. Applications targeting M2-like tumor-associated macrophages (TAMs) improve outcome in solid tumors. Considerable differences are detected between leukemia-associated macrophages (LAMs) and TAMs. However, application to induce M1 characteristics in heterogeneous LAMs has not been established. Here we analyzed clinical relevance of macrophage phenotypes in human acute myeloid leukemia (AML), studied phenotypic evolution of bone marrow (BM) and spleen (SP) LAMs in mouse AML and T cell acute lymphoblastic leukemia (T-ALL) models, explored mechanism leading to different LAM phenotypes and tried to eliminate pro-leukemic effects by inducing M1 characteristics. The results showed that more M2-like LAMs but not total LAMs correlated with worse prognosis in AML patients. Heterogeneity of LAM activation in tissue-specific leukemic microenvironments was observed in both AML and ALL models, SP LAMs evolved with more M2 characteristics while BM LAMs with more M1 characteristics. Furthermore, IRF7 contributed to M1 characteristics through the activation of SAPK/JNK pathway. Moreover, targeting IRF7-SAPK/JNK pathway to induce M1 characteristics in LAMs contributed to prolonged survival in leukemia mice. Our study provides the potential target for macrophage based immuno-therapy strategy against leukemia.

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Background Infection in patients with acute pancreatitis, especially severe acute pancreatitis patients, is a common and important phenomenon, and the distributions and drug resistance profiles of bacteria causing biliary infection and related risk factors are dynamic. We conducted this study to explore the characteristics of and risk factors for bacterial infection in the biliary tract to understand antimicrobial susceptibility, promote the rational use of antibiotics, control multidrug-resistant bacterial infections and provide guidance for the treatment of acute pancreatitis caused by drug-resistant bacteria. Methods The distribution of 132 strains of biliary pathogenic bacteria in patients with acute pancreatitis from January 2016 to December 2020 were analyzed. We assessed drug resistance in the dominant Gram-negative bacteria and studied the drug resistance profiles of multidrug-resistant bacteria by classifying Enterobacteriaceae and nonfermentative bacteria. We then retrospectively analyzed the clinical data and risk factors associated with 72 strains of Gram-negative bacilli, which were divided into multidrug-resistant bacteria (50 cases) and non-multidrug-resistant bacteria (22 cases). Results The main bacteria were Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli had a 66.67% detection rate. Acinetobacter baumannii had more than 50.00% drug resistance to carbapenems, ESBL-producing Klebsiella pneumoniae had 100.00% drug resistance, and Pseudomonas aeruginosa had 66.67% resistance to carbapenems. Multivariate logistic regression analysis suggested that the administration of third- or fourth-generation cephalosporins was an independent risk factor for Gram-negative multidrug-resistant biliary bacterial infection in acute pancreatitis patients. Conclusion Drug resistance among biliary pathogens in acute pancreatitis patients remains high; therefore, rational antimicrobial drug use and control measures should be carried out considering associated risk factors to improve diagnosis and treatment quality in acute pancreatitis patients.

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F-box proteins serve as the substrate recognition subunit for the SCF E3 ubiquitin ligases. These ligases ubiquitinate specifically phosphorylated substrates and play a pivotal role in the regulation of various signal transduction pathways, which, in turn, are essential for many aspects of tumorigenesis. However the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown. Here, we found two transcript variants (Fbxw11c and Fbxw11d) expressed in mouse bone marrow. More importantly, the expression of Fbxw11 in normal hematopoietic stem cells (HSCs) from Notch1-induced leukemia mice was higher than that from control mice. In order to investigate the role of Fbxw11 in leukemia, we established L1210 cell lines over-expressing Fbxw11c or Fbxw11d respectively using the lentivirus system. Over-expression of both Fbxw11 variants stimulated the proliferation of L1210 cells in vitro by cell counting and MTT assay. The tumor xenografts model with over-expression of Fbxw11c or Fbxw11d in DBA/2 mice was further established. Over-expression of both variants resulted in the increased tumor growth in vivo. Investigation of the molecular mechanism revealed that the increased cell proliferation was not due to decrease in cell apoptosis but due to increase in cell cycle. Further studies showed that overexpression of both Fbxw11c and Fbxw11d caused the activation of NF-κB signaling pathway. These findings suggest the important role of Fbxw11 in regulating the development of leukemia and indicate a potent rationale for developing Fbxw11 as a potential therapeutic target against leukemia. Citation Format: Lina Wang, Jinfeng Liao, Xiao Yang, Wenli Feng, Shayan Chen, Guoguang Zheng. Fbxw11 promotes leukemia development by activating the NF-κB signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4433. doi:10.1158/1538-7445.AM2014-4433