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Chemical Screening Identified Compounds That Trigger Differentiation and Augment ATRA-Induced Myeloid Cell Differentiation

ABSTRACT: Chemical Screening Identified Compounds That Trigger Differentiation and Augment ATRA-Induced Myeloid Cell Differentiation

PROVIDER: PRJNA1111121 | ENA |

REPOSITORIES: ENA

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Chemical Screening Identified Compounds That Trigger Differentiation and Augment ATRA-Induced Myeloid Cell Differentiation

Project description:Acute myeloid leukemia (AML) is a blood cancer characterized by abnormal proliferation and differentiation arrest of myeloid progenitor cells. Clinical treatment of AMLs remains challenging. Promoting AML cell differentiation is a valid therapeutic strategy. But most AMLs lack effective differentiation drugs. In this study, we generated Tg(drl:hoxa9) zebrafish, which drives hoxa9 overexpression in hematopoietic cells and exhibits myeloid differentiation arrest. Using Tg(drl:hoxa9) embryos, we performed a chemical screen and identified four FDA-approved drugs, ethacrynic acid, khellin, oxcarbazepine and alendronate, that efficiently restored myeloid differentiation in embryos. The four drugs also induced the differentiation of AML cells, with ethacrynic acid being the most effective. By RNA-seq analysis, we found that during induction of differentiation, ethacrynic acid activates the IL-17 and MAPK signaling pathways, which are known to promote granulopoiesis. Furthermore, we found that ethacrynic acid enhances all-trans retinoic acid (ATRA)-induced myeloid differentiation, and the two signaling are convergent on the IL-17/MAPK pathways. Inhibition of IL-17 /MAPK pathways impairs ethacrynic acid and ATRA-induced differentiation. In addition, we showed that ethacrynic acid is less toxic to embryonic development and less disruptive to normal hematopoietic processes than ATRA. Thus, the combination of ethacrynic acid and ATRA may have a broader clinical application. In conclusion, through zebrafish-aided screening, our study identified four drugs repurposed to induce AML differentiation and provided new agents for AML therapy.

2025-05-01 | GSE267350 | GEO

CAMKK and CRAC channel regulate autophagy, differentiation and apoptosis in acute promylocytic leukemia cells treated by ATRA

Project description:ATRA is an active metabolite of vitamin A that is frequently used for the treatment of acute promyelocytic leukemia (APL) patients. Despite the success of this treatment, some APL patients are refractory or relapse. This emphasis the need for new therapeutic strategies aiming to improve the anti-cancer effect of ATRA. We and other have previously shown that autophagy is activated during ATRA-induced granulocytic differentiation of acute promyelocytic leukemia cells. Although the transcription effect of ATRA on autophagy has been well-documented, little is known on the post-transcription/ post-translational regulation autophagy in response to ATRA. Given the importance of calcium ions in the control of autophagy, we hypothesized that calcium ions are involved in the initiation of autophagy by ATRA in APL cells. We thus examined how ATRA regulate intracellular calcium and sense perturbation of Ca2+ responses to autophagy, differentiation and cell death in APL cells.

2021-11-24 | PXD026904 | Pride

Effects of fucosylation inhibitors on ATRA differentiation in myeloid leukemia cells

Project description:Differentiation therapy with all-trans retinoic acid (ATRA) is well established for acute promyelocytic leukemia (APL). However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we challenged glycosylation inhibitor to obtain better efficiency than ATRA alone. As a result, we found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) with ATRA have profound effect for differentiation, shown by expression changes of differentiation markers CD11b, CD11c, with significant morphological change in NB4 and HL-60 cells. From lectin blot assay, we found that ATRA or 6AF alone could decrease core fucosylation, the combination of these two agents efficiently decreases the expression of core fucosylation. To reveal molecular mechanisms to reveal 6AF effect for ATRA induced differentiation, we next performed microarray analysis using NB4 cells. From pathway analysis using DAVID software, we found that C-type lectin receptor (CLR) signaling pathway was enriched as high significance. From real time PCR analysis, using NB4 and HL-60 cells, FcRI, CLEC6A, CASP1, IL-1, EGR2/3, the components of CLR, and Akt, were indeed upregulated by 6AF in ATRA induced differentiation. These suggest that the involvement of CLR signaling pathway in 6AF effect of ATRA induced differentiation.

2023-06-08 | GSE234103 | GEO

Activation of CASP1 induces AML cell pyroptosis and sensitizes to ATRA treatment

Project description:Acute myeloid leukemia (AML) is characterized by the accumulation of immature leukemic blasts. The application of all-trans retinoic acid (ATRA) treatments have markedly transformed acute promyelocytic leukemia (APL, the M3 subtype of AML) to a highly manageable disease, and research strategies that seek to extend the application of ATRA-based treatment to other AML subtypes are an important area of investigation. Here, we found CASP1/GSDMD was lower expressed in APL and most other subtypes of primary de novo AML patients and increased in ATRA-treated APL cells. We showed that ATRA increased and activated CASP1 to trigger pyroptosis and differentiation of APL cells. Mechanistically, ATRA could induce CASP1 expression via IFNγ/STAT1 in APL and non-APL AML cells, while do not activate CASP1 in non-APL AML cells. Accordingly, pharmacological activation of CASP1 by Val-boroPro (DPP8/9 inhibitor) enhanced pyroptosis and differentiation induced by ATRA in AML cells. Moreover, the combination of ATRA and Val-boroPro enhanced anti-leukemia activity in primary AML cells. Our study demonstrates that the ATRA-mediated anti-leukemia effect requires a functional activated CASP1 and provides a highly attractive therapeutic strategy for the treatment of AML.

2024-12-01 | GSE190341 | GEO

The Study of ATRA-Induced Differentiation of the HL-60 Cell Line

Project description:Shotgun mass-spectrometric experiment was performed with HL-60 cells induced to differentiation at 0, 3, 24, 48 and 96h after ATRA treatment. Obtained data has been used for label-free quantification by SPIRE platform based on spectral count. Results on proteome profiling were used for up-stream regulator search in geneXplain platform (http://genexplain.com/).

2021-09-07 | PXD006768 | Pride

Human HL-60 Cells: all-trans retinoic acid (ATRA) vs. ATRA plus arsenic trioxide (ATO)

Project description:Transcriptional profiling of human leukemia　HL-60 cells comparing ATRA treated HL-60 cells with ATRA plus ATO. Goal was to determine the effects of ATO on ATRA induced differentiation of HL-60 cells.

2015-03-31 | GSE67420 | GEO

Human HL-60 Cells: all-trans retinoic acid (ATRA) vs. ATRA plus arsenic trioxide (ATO)

Project description:Transcriptional profiling of human leukemia?HL-60 cells comparing ATRA treated HL-60 cells with ATRA plus ATO. Goal was to determine the effects of ATO on ATRA induced differentiation of HL-60 cells. Two-condition experiment, ATRA vs. ATRA plus ATO treated HL-60 cells.

2015-03-31 | E-GEOD-67420 | biostudies-arrayexpress

Expressional Alterations in Ultra-Conserved Non-Coding RNA in Response to ATRA-induced Differentiation

Project description:Effect of ATRA-induced differentiation on the expression of transcribed ultra-conserved regions in neuroblastoma cell lines.

2012-08-01 | E-MEXP-2930 | biostudies-arrayexpress

Palbociclib synergizes with ATRA to induce differentiation in AML

Project description:Palbociclib synergizes with ATRA to induce differentiation in AML

| PRJEB63304 | ENA

Fulica atra

Project description:Fulica atra

| PRJNA815160 | ENA