The role of autophagy in targeted therapy for acute myeloid leukemia

Du, Wenxin; Xu, Aixiao; Huang, Yunpeng; Cao, Ji; Zhu, Hong; Yang, Bo; Shao, Xuejing; He, Qiaojun

doi:10.1080/15548627.2020.1822628

Cited by 58 publications

(68 citation statements)

References 133 publications

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“…Increasing evidence has shown that autophagy is a key mechanism in leukemogenesis and chemoresistance, and this has made it an attractive therapeutic target in research in recent years (13,14). A number of autophagy-inducing agents, such as arsenic trioxide, vitamin D3, eupalinin A, APO866, and platonin, have been developed to initiate the death of leukemic cells (15). A variety of essential genes are involved in the machinery of autophagy to control the balance of catabolic processes (16).…”

Section: Introductionmentioning

confidence: 99%

“…A variety of essential genes are involved in the machinery of autophagy to control the balance of catabolic processes (16). Research on the role of autophagy in the progression of AML and responses to the treatment of patients has focused on one or more autophagy-related genes (ARGs) (15), and few studies have sought to systematically clarify the potential roles of expressions of these ARGs in predicting the prognoses of AML patients.…”

Section: Introductionmentioning

confidence: 99%

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Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature

Zhang

et al. 2021

Front. Immunol.

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature

Zhang

et al. 2021

Front. Immunol.

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“…Abnormal DNA methylation at the C5 position of the cytosine catalyzed by DNMTs is not only related to silencing of many tumor suppressor genes, but also to other diseases. Small molecule inhibitors of DNMTs are the most widely used epigenetic therapies for cancer treatment, mainly for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) ( Khan et al, 2013 ; Du et al, 2020 ). DNMT is usually overexpressed in various cancer tissues and cell lines.…”

Section: Writersmentioning

confidence: 99%

Methylation Landscape: Targeting Writer or Eraser to Discover Anti-Cancer Drug

et al. 2021

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Cancer is a major global health challenge for our health system, despite the important pharmacological and therapeutic discoveries we have seen since past 5 decades. The increasing prevalence and mortality of cancer may be closely related to smoking, exposure to environmental pollution, dietary and genetic factors. Despite significant promising discoveries and developments such as cell and biotechnological therapies a new breakthrough in the medical field is needed to develop specific and effective drugs for cancer treatment. On the development of cell therapies, anti-tumor vaccines, and new biotechnological drugs that have already shown promising effects in preclinical studies. With the continuous enrichment and development of chromatin immunoprecipitation sequencing (ChIP-seq) and its derivative technologies, epigenetic modification has gradually become a research hotspot. As key ingredients of epigenetic modification, Writers, Readers, Erasers have been gradually unveiled. Cancer has been associated with epigenetic modification especially methylation and therefore different epigenetic drugs have been developed and some of those are already undergoing clinical phase I or phase II trials, and it is believed that these drugs will certainly assist the treatment in the near future. With respect to this, an overview of anti-tumor drugs targeting modified enzymes and de-modified enzymes will be performed in order to contribute to future research.

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“…Recently, extensive molecular characterization studies have led to a deeper understanding of the complex AML heterogeneity and to the development of targeted therapies [ 2 ]. Besides the improvement in the genetic knowledge of AML physiopathology, several important cellular mechanisms such as autophagy have been identified to be deregulated in AML and involved in its development and therapeutic resistance [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagy a Close Relative of AML Biology

Joffre

Ducau

Poillet-Perez

et al. 2021

Biology

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Autophagy, which literally means “eat yourself”, is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies.

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The role of autophagy in targeted therapy for acute myeloid leukemia

Cited by 58 publications

References 133 publications

Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature

Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature

Methylation Landscape: Targeting Writer or Eraser to Discover Anti-Cancer Drug

Autophagy a Close Relative of AML Biology

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