Abstract
Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies that has an unfavorable outcome and a high rate of relapse. Autophagy plays a vital role in the development of and therapeutic responses to leukemia. This study identifies a potential autophagy-related signature to monitor the prognoses of patients of AML. Transcriptomic profiles of AML patients (GSE37642) with the relevant clinical information were downloaded from Gene Expression Omnibus (GEO) as the training set while TCGA-AML and GSE12417 were used as validation cohorts. Univariate regression analyses and multivariate stepwise Cox regression analysis were respectively applied to identify the autophagy-related signature. The univariate Cox regression analysis identified 32 autophagy-related genes (ARGs) that were significantly associated with the overall survival (OS) of the patients, and were mainly rich in signaling pathways for autophagy, p53, AMPK, and TNF. A prognostic signature that comprised eight ARGs (BAG3, CALCOCO2, CAMKK2, CANX, DAPK1, P4HB, TSC2, and ULK1) and had good predictive capacity was established by LASSO–Cox stepwise regression analysis. High-risk patients were found to have significantly shorter OS than patients in low-risk group. The signature can be used as an independent prognostic predictor after adjusting for clinicopathological parameters, and was validated on two external AML sets. Differentially expressed genes analyzed in two groups were involved in inflammatory and immune signaling pathways. An analysis of tumor-infiltrating immune cells confirmed that high-risk patients had a strong immunosuppressive microenvironment. Potential druggable OS-related ARGs were then investigated through protein–drug interactions. This study provides a systematic analysis of ARGs and develops an OS-related prognostic predictor for AML patients. Further work is needed to verify its clinical utility and identify the underlying molecular mechanisms in AML.
Highlights
Acute myeloid leukemia (AML) is one of the most aggressive blood malignancies that is characterized by a heterogeneity of molecular abnormalities and the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood [1, 2]
The predictive accuracy of the risk signature was analyzed on the validation set, and the results suggest that it is an effective predictor of patient outcomes that is independent of the clinical parameters used to monitor them
The expressions of 32 autophagy-related genes (ARGs) were found to be significantly associated with the Overall Survival (OS) of the AML patients (Table 1)
Summary
AML is one of the most aggressive blood malignancies that is characterized by a heterogeneity of molecular abnormalities and the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood [1, 2]. Autophagy is a complex multistep self-digestive cellular process that is essential for the survival, differentiation, and homeostasis of cells [5]. It sequesters damaged organelles/ proteins, invading pathogens, and macromolecules in an autophagosome coated with a double membrane. A variety of roles of autophagy have been identified in hematopoietic disease. It is required for maintaining the functions of hematopoietic stem cells [9] and T-lymphoid lineages [10, 11], and for responses to extracellular cytokine stimuli [12]. Increasing evidence has shown that autophagy is a key mechanism in leukemogenesis and chemoresistance, and this
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