Mutation profile and associated clinical features in Chinese patients with cytogenetically normal acute myeloid leukemia.

INTRODUCTION: Cytogenetically normal acute myeloid leukemia (CN-AML), which accounted for nearly half of total AML patients, is a highly heterogeneous subset of AML. The specific genetic profile and the ethnic features of CN-AML are worth to be studied. METHODS: Using deep sequencing technology, we detected the mutation pattern of 39 genes in 152 Chinese CN-AML patients and analyzed their clinical features. RESULTS: A total of 503 mutations of 39 genes were identified in 145 (95.4%) patients, with the median number of 3 mutations per case. Nine genes (NPM1, CEBPA, DNMT3A, GATA2, NRAS, TET2, FLT3, IDH2, and WT1) mutated in more than 10% patients. Function groups of myeloid transcription factors, activated signaling, and DNA methylation were most affected. The distribution of variant allele frequencies (VAF) of recurrent genes was different among functional groups. High mutation rates of CEBPA and GATA2 together with the low frequency of FLT3-ITD mutation seemed to be the distinct characteristics of Chinese patients. Furthermore, CEBPAbi and GATA2 were found to mutate most in M2 subtype, while NPM1 and DNMT3A mutated more in M4 and M5. The prognostic analysis identified CEBPAmo mutation as an inferior factor. FLT3-ITD, TP53, DNMT3A, CEBPAmo, and WT1 mutations were selected as high-risk markers to identify the CN-AML patients with poor prognosis. CONCLUSION: Our study provided the valuable information of ethnic genetic characteristics and the clinical relevance of Chinese CN-AML patients.

[Effects of tumor necrosis factor-α monoclonal antibody on nuclear factor-κB activation and inducible nitric oxide synthase expression in rats with silicotic fibrosis].

Objective: To investigate the effects of tumor necrosis factor-α (TNF-α) monoclonal anti-body on nuclear factor-κB (NF-κB) activation and inducible nitric oxide synthase (iNOS) expression in rats with pulmonary fibrosis induced by silica dust. Methods: A total of 48 male Wistar rats were randomly divided into intervention group, silica dust exposure group, and control group, with 16 rats in each group. The rats in the intervention group were given intratracheal injection of 50 mg silicon dioxide dust once to establish a rat model and then treated with subcutaneously injected TNF-α monoclonal antibody 15 mg/kg for 5 consecutive days at 2-6 days after the establishment of the model. The rats in the silica dust exposure group were treated with the same method to establish the model and then given subcutaneous injection of the same volume of normal saline. The rats in the control group were given intratracheal and subcutaneous injection of normal saline. In both groups, 8 rats each were sacrificed at 7 and 14 days after the establishment of the model. Hematoxylin-eosin staining or Masson staining was used to observe morphological changes in lung tissue, ELISA was used to measure the serum level of TNF-α, IHC was used to measure the expression of NF-κBp65 in lung tissue, Western blot was used to measure the protein expression of I-κB in lung tissue, and RT-qPCR was used to measure the transcriptional level of iNOS mRNA in lung tissue. Results: Compared with the control group, the silica dust exposure group had significant increases in the lung inflammation score (3.375±1.061 and 2.500±0.535) , serum TNF-α level (86.405±20.494 and 77.064±11.829) , absorbance of cells with positive NF-κBp65 in lung tissue (0.297±0.05 and 0.287±0.039) , and mRNA expression of iNOS (12.906±0.590 and 12.600±0.517) at 7 and 14 days after dust exposure, a significant increase in pulmonary fibrosis score at 14 days (3.250±0.707) , and significant reductions in the protein expression of I-κB at 7 and 14 days (0.579±0.141 and 0.748±0.081) (P<0.05) . Compared with the silica dust exposure group, the intervention group had significant reductions in the lung inflammation score at 7 days (2.375±1.061) , pulmonary fibrosis score at 14 days (2.375±1.061) , serum level of TNF-α at 7 and 14 days (66.565±19.850 and 58.734±16.335) , absorbance of cells with positive NF-κBp65 in lung tissue at 7 and 14 days (0.248±0.028 and 0.238±0.027) , and mRNA expression of iNOS at 7 and 14 days (11.656±0.405 and 12.025±0.618) , as well as significant increases in the protein expression of I-κB at 7 and 14 days (0.802±0.165 and 0.888±0.144) (P<0.05) . Conclusion: TNF-α monoclonal antibody can inhibit the activation of the NF-κB signaling pathway and down-regulate the expression of iNOS, and thus exerts a certain protective effect on lung tissue in rats with pulmonary fibrosis induced by silica dust.