Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy

Jin, Jing; Britschgi, Adrian; Schläfli, Anna M.; Humbert, Magali; Shan-Krauer, Deborah; Batliner, Jasmin; Federzoni, Elena; Ernst, Marion; Torbett, Bruce E.; Yousefi, Shída; Simon, Hans‐Uwe; Tschan, Mario P.

doi:10.1155/2018/1482795

Cited by 55 publications

(68 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data were consistent with studies showing that defective autophagy lead to a distinct reduction in granules and nuclear lobularization, as well as defective differentiation and dysfunction of neutrophils. [33][34][35] To further determine the role of autophagy in A. fumigatus keratitis, the levels of inflammatory cytokines IL-1β, IL-18, HMGB1, TNF-α, and IL-10 were detected after treatment with 3-MA, CQ, and rapamycin. Results indicated that treatment with 3-MA and CQ significantly increased mRNA and protein levels of IL-1β, IL-18, HMGB1, and TNF-α, and reduced the expression of IL-10 in comparison with infected control corneas.…”

Section: Discussionmentioning

confidence: 99%

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Cui

Lin

et al. 2020

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Li C, Li C, Lin J, et al. The role of autophagy in the innate immune response to fungal keratitis caused by Aspergillus fumigatus infection. Invest Ophthalmol Vis Sci. 2020;61(2):25. https://doi.org/10.1167/iovs.61.2.25 PURPOSE.To determine the role of autophagy in the innate immune response to fungal keratitis (FK) caused by Aspergillus fumigatus infection. METHODS.Corneal samples obtained from patients and mice with FK were visualized via transmission electron microscopy (TEM). Autophagy-related proteins LC3B-II, Beclin-1, LAMP-1, and p62 in A. fumigatus-infected corneas of C57BL/6 mice were tested by Western blot. After treatment with autophagy inhibitors 3-methyladenine (3-MA), chloroquine (CQ), or inducer rapamycin, autophagy-related proteins were detected by Western blot. Corneas were photographed with slit lamp microscopy and pathological changes were observed by hematoxylin and eosin staining. Polymorphonuclear neutrophilic leukocytes (PMNs) were assessed by immunofluorescent staining and observed under TEM. The levels of CXCL-1, IL-1β, HMGB1, IL-18, TNF-α, and IL-10 were tested by reverse transcription polymerase chain reaction and Western blot. The quantification of fungal loads was detected and photographed. RESULTS.The accumulation of autophagosomes in corneas of patients and mice with FK was observed with TEM. The expression of LC3B-II, Beclin-1, and LAMP-1 was elevated in corneas after fungal infection, whereas p62 was reduced. Treatment with 3-MA or CQ upregulated clinical scores, pathological changes, and the expression of CXCL-1, IL-1β, HMGB1, IL-18, and TNF-α except IL-10. The morphology of PMNs was changed and PMN recruitment was increased in mice corneas treated with 3-MA or CQ, whereas rapamycin reduced the inflammatory response to keratitis. These results were statistically significant. CONCLUSIONS. A. fumigatus infection increases the expression of autophagy in corneas.Autophagy plays an anti-inflammatory role in the innate immune response to A. fumigatus keratitis.

show abstract

Section: Discussionmentioning

confidence: 99%

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Cui

Lin

et al. 2020

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…The complexity of the interplay between autophagy and disease progression in blood cancer is well exemplified in acute myeloid leukemia (AML) studies. Autophagy deregulation has been described in AML where ATG gene expression is frequently repressed [90,[94][95][96][97]. Autophagy abrogation, by deletion of key ATG genes, leads to leukemia initiation and progression in mouse models [96][97][98][99].…”

Section: Leukemia and Lymphomasmentioning

confidence: 99%

“…Autophagy deregulation has been described in AML where ATG gene expression is frequently repressed [90,[94][95][96][97]. Autophagy abrogation, by deletion of key ATG genes, leads to leukemia initiation and progression in mouse models [96][97][98][99]. Remarkably, some studies showed a high frequency of AML patients, particularly those with complex karyotypes, carrying heterozygous deletions, missense mutations or copy number variations of ATG genes [97,100,101].…”

Section: Leukemia and Lymphomasmentioning

confidence: 99%

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

Humbert

Morán

Cruz‐Ojeda

et al. 2020

Biology

Self Cite

View full text Add to dashboard Cite

Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples.

show abstract

“…The PML-RARα phenotype is also characterized by the downregulation of autophagy-related genes (ATGs) (i.e., ULK1, BECN1, ATG14, ATG5, ATG7, ATG3, ATG4B and ATG4C) [29][30][31]. Autophagy or "self-eating" is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles [32].…”

Section: Apl Pathophysiologymentioning

confidence: 99%

“…The ubiquitinylation and subcellular localization of PTEN are regulated by a HAUSP-PML network [27], we demonstrated that PML-RARα directly suppresses PTEN expression [28]. The lack of PTEN anticancer control could play a pivotal role in favoring the emergence, survival and proliferation of damaged stem cells, allowing the accumulation of additional genetic events towards leukemogenesis.The PML-RARα phenotype is also characterized by the downregulation of autophagy-related genes (ATGs) (i.e., ULK1, BECN1, ATG14, ATG5, ATG7, ATG3, ATG4B and ATG4C) [29][30][31]. Autophagy or "self-eating" is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles [32].…”

mentioning

confidence: 99%

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

Noguera

Catalano

Banella

et al. 2019

Preprint

View full text Add to dashboard Cite

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

show abstract

Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy

Cited by 55 publications

References 71 publications

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

Contact Info

Product

Resources

About