Identification of a venetoclax-resistance prognostic signature base on 6-senescence genes and its clinical significance for acute myeloid leukemia

BackgroundSatisfactory responses can be obtained for acute myeloid leukemia (AML) treated by Venetoclax (VEN)-based therapy. However, there are still quite a few AML patients (AMLs) resistant to VEN, and it is critical to understand whether VEN-resistance is regulated by senescence.MethodsHere, we established and validated a signature for predicting AML prognosis based on VEN resistance-related senescence genes (VRSGs). In this study, 51 senescence genes were identified with VEN-resistance in AML. Using LASSO algorithms and multiple AML cohorts, a VEN-resistance senescence prognostic model (VRSP-M) was developed and validated based on 6-senescence genes.ResultsAccording to the median score of the signature, AMLs were classified into two subtypes. A worse prognosis and more adverse features occurred in the high-risk subtype, including older patients, non-de novo AML, poor cytogenetics, adverse risk of European LeukemiaNet (ELN) 2017 recommendation, and TP53 mutation. Patients in the high-risk subtype were mainly involved in monocyte differentiation, senescence, NADPH oxidases, and PD1 signaling pathway. The model’s risk score was significantly associated with VEN-resistance, immune features, and immunotherapy response in AML. In vitro, the IC50 values of ABT-199 (VEN) rose progressively with increasing expression of G6PD and BAG3 in AML cell lines.ConclusionsThe 6-senescence genes prognostic model has significant meaning for the prediction of VEN-resistance, guiding personalized molecularly targeted therapies, and improving AML prognosis

Effects of sexual steroids on the expression of foxl2 in Gobiocypris rarus

Gobiocypris rams is an emerging fish model for aquatic toxicology in China as it is sensitive to environmental hormone disruptors. Exogenous sex steroids can affect sex differentiation and the expression of sex-related genes. Foxl2, a member of forkhead-box transcription factor family, is the key gene for ovary development and its mutation causes the blepharophimosis ptosis epicanthus inversus syndrome in human. We find that two foxl2 genes exist in fish genome, one is foxl2, and the other is foxl2b. Here, we reported the isolation and expression of foxl2 in G. rams. G. rarus foxl2 cDNA is 1700 bp in length with a 921 bp of open reading frame encoding 306 amino acids containing the typical FM-domain. Semi-quantitative RT-PCR revealed its predominant expression in the eye, brain, gill and gonads. Moreover, the expression level in the ovary was significantly higher than that in the testis. Quantitative RT-PCR showed that foxl2 was up regulated after treatment with estradiol and was down regulated with 2-methyl-testosterone. These results suggested that Foxl2 plays an important role in female development of G. rams, foxl2 mRNA expression is regulated by downstream sex hormones, and foxl2 can be used as a molecular indicator monitoring the environmental endocrine disruptors. (C) 2011 Elsevier Inc. All rights reserved