AUTHOR=Ke Peng , Xie Jundan , Xu Ting , Chen Meiyu , Guo Yusha , Wang Ying , Qiu Huiying , Wu Depei , Zeng Zhao , Chen Suning , Bao Xiebing 

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1302356

DOI=10.3389/fonc.2023.1302356

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Satisfactory 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.</p></sec><sec><title>Methods</title><p>Here, 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.</p></sec><sec><title>Results</title><p>According 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-<italic>de novo</italic> AML, poor cytogenetics, adverse risk of European LeukemiaNet (ELN) 2017 recommendation, and <italic>TP53</italic> 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. <italic>In vitro</italic>, the IC50 values of ABT-199 (VEN) rose progressively with increasing expression of <italic>G6PD</italic> and <italic>BAG3</italic> in AML cell lines.</p></sec><sec><title>Conclusions</title><p>The 6-senescence genes prognostic model has significant meaning for the prediction of VEN-resistance, guiding personalized molecularly targeted therapies, and improving AML prognosis.</p></sec>