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

Abstract

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.

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…However, it should be emphasized that the differentiation-associated resistance is an important, but not the only, mechanism of venetoclax resistance. The main observations with regards to monocytic differentiation and venetoclax resistance are summarized in Table 4 and are discussed in detail in this main section [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ].…”

“…First, FAB-M4/M5 monocytic AML is associated with venetoclax resistance, but the association seems to be weaker for high-risk/relapsed AML [ 160 , 164 ]. Second, decreased reliance on Bcl-2 for survival and metabolic regulation is one of the mechanisms behind the decreased responsiveness in monocytic AML [ 164 , 165 , 166 , 167 ], but other mechanisms, including more general mechanisms such as mechanisms associated with specific genetic abnormalities, also contribute even in monocytic AML [ 160 ]. Third, differentiation-associated decreased reliance on Bcl-2 for metabolic regulation and survival is not a specific mechanism for monocytic differentiation.…”

“…Regulation of senescence together with PD1 signaling and NADP oxidase activity seems to be involved in the clinical venetoclax resistance associated with monocytic differentiation [166].…”