Enhancing autophagy protects platelets in immune thrombocytopenia patients

Wang, Chunyan; Ma, Sai; Bi, Shaojie; Su, Le; Huang, Shuya; Jiang, Miao; Ma, Chao; Gao, Chengjiang; Hou, Ming‐Feng; Peng, Jun

doi:10.21037/atm.2019.03.04

Cited by 30 publications

(32 citation statements)

References 37 publications

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“…The MAMDC4 protein is associated with a unique endocytic mechanism observed in the intestine of mammals [38], which may be related to the autophagy activities of platelets from ITP patients [12]. Furthermore, microRNAs act by targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and the subsequent downregulation of insulin-like growth factor 2 (IGF-2) causes inhibition of the PI3K/Akt pathway, which is involved in the mesenchymal stem cell (MSC) deficiency seen in ITP [39].…”

Section: Discussionmentioning

confidence: 99%

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Gene mutations in members of the PI3K/Akt signalling pathway are related to immune thrombocytopenia pathogenesis

Sun

Zhang

et al. 2020

Preprint

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PurposeImmune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. In this research, we conducted an in-depth genomic analysis of a cohort of patients and elucidated the molecular features associated with the pathogenesis of ITP.MethodHigh-molecular-weight genomic DNA was extracted from freshly frozen bone marrow blood mononuclear cells (BMBMCs) from 20 active ITP patients. Next, the samples were subjected to molecular genetic analysis by whole-exome sequencing (WES), and the results were confirmed by Sanger sequencing. The signalling pathways and cellular processes associated with the mutated genes were identified with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.ResultsThe results of this study revealed 3,998 missense mutations involving 2,269 genes in more than 10 individuals. Some unique genetic variants, including phosphatase and tensin homologue (PTEN), insulin receptor (INSR) and coagulation factor C homology (COCH) variants, were the most associated with the pathogenesis of ITP. Functional analysis revealed that these gene mutations mainly affected the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) signalling pathways (signal transduction) and platelet activation (immune system).ConclusionsOur findings demonstrate the functional connections between these gene variants and ITP. Although the underlying mechanisms and the impact of these genetic variants remain to be revealed through further investigation, the application of next-generation sequencing in ITP in this paper is valuable for revealing the genetic mechanisms of ITP.SummaryImmune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. DNA mutation profile of ITP patient bone marrow samples (n=20) were investigated by using next-generation sequencing (NGS), and then confirmed by sanger sequencing method. Our results showed PTEN, INSR and COCH were mutated in all ITP patients. Functional analysis revealed these mutation genes mainly participate PI3K/Akt signaling pathways and platelet activation. These results suggest that genetic alterations might be involved in the pathogenesis of ITP.

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Section: Discussionmentioning

confidence: 99%

“…Platelet autophagy is regulated through the PI3K/Akt/mTOR signalling pathway by phosphatase and tensin homologue (PTEN) in ITP. Elevated platelet autophagy may prolong the life span of platelets from ITP patients by inhibiting platelet apoptosis and improving platelet viability [12].…”

Section: Introductionmentioning

confidence: 99%

Gene mutations in members of the PI3K/Akt signalling pathway are related to immune thrombocytopenia pathogenesis

Sun

Zhang

et al. 2020

Preprint

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“…Wang et al through enhanced autophagy-related protein and autophagy ux in PI3K/Akt/mTOR signaling pathway, inhibiting apoptosis and improving platelet viability, thereby alleviating platelet destruction and prolonging the life span of platelets from ITP patients [12]. Furthermore, microRNAs acts through targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and the subsequent downregulation of insulin-like growth factor 2 (IGF-2) causes inhibition of the PI3K/Akt pathway, which is involved in the process of MSC(mesenchymal stem cells de ciency) in ITP [39].We reported previously that abnormal expression of multiple proteins in PI3K/Akt pathway in patient groups compared with control groups using protein pro les technology [18].…”

Section: Discussionmentioning

confidence: 99%

Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis

Sun

Liu

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. In this research, we conducted an in-depth genomic analysis of a cohort of patients and elucidate molecular features associated with disease pathogenesis of ITP. High-molecular-weight genomic DNA was extracted from freshly frozen BMBMCs (bone marrow blood mononuclear cell) in 20 active ITP patients. After this, the samples were subjected to molecular genetic analysis by whole-exome sequencing technique (WES) then, confirmed by sanger sequencing method. The enriched signaling pathway analysis and cellular processes associated with the mutated genes was performed with gene mapping to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The results of this study showed that there were 3998 missense mutations involving 2269 genes in more than 10 individuals. Unique genetic variants including PTEN, INSR and COCH were the most associated with the pathogenesis of ITP. Functional analysis revealed these mutation genes mainly affect Phosphatidylinositol 3 kinase/serine/threonine kinase B (PI3K/Akt) signaling pathways (signal transduction) and platelet activation (immune system). Our finding further demonstrates the functional connections between these variant genes and ITP. Although the substantial mechanism and the impact of genetic variation are required further investigation, the application of next generation sequencing in ITP in this paper is a valuable method to reveal the genetic susceptibility.

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“…The pathogenesis of immune thrombocytopenic purpura (ITP) includes abnormal activation of autoreactive T and B cells, which leads to immune destruction of platelets, providing a theoretical basis for the application of rapamycin in ITP. Wang CY et al ( 100 ) found that platelet autophagy was diminished in ITP patients, and platelet autophagy in ITP was regulated by the PI3K/Akt/mTOR pathway. Rapamycin induced autophagy and alleviated the destruction of ITP platelets ( 100 ).…”

Section: Applications In Non-malignant Hemopathiesmentioning

confidence: 99%

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside

et al. 2021

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The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases—either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist’s toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.

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Enhancing autophagy protects platelets in immune thrombocytopenia patients

Cited by 30 publications

References 37 publications

Gene mutations in members of the PI3K/Akt signalling pathway are related to immune thrombocytopenia pathogenesis

Gene mutations in members of the PI3K/Akt signalling pathway are related to immune thrombocytopenia pathogenesis

Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside

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