Synergistic Potential of CDK4/6 Inhibitors and ATRA in non-APL AML.
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ABSTRACT:
PROVIDER: PRJNA1235689 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32684178.fastq.gz | Fastqsanger.gz | |||
| SRR32684183.fastq.gz | Fastqsanger.gz | |||
| SRR32684184.fastq.gz | Fastqsanger.gz | |||
| SRR32684187.fastq.gz | Fastqsanger.gz |
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Project description:Background: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by diverse genetic abnormalities. The standard of care remains to be chemotherapy and stem cell transplantation. In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) has significantly improved outcomes. Despite this, the success of ATRA has yet to be transferred to non-APL AML. Exploring combinations to enhance the efficacy of ATRA in non-APL AML remains a key focus. Objective: To investigate the therapeutic effect of ATRA in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in non-APL AML. Methods: Non-APL AML cells and primary patient samples were treated with ATRA and CDK4/6 inhibitors. Key outcomes included differentiation, proliferation, cell viability, and colony-forming capacity. Combination synergy was evaluated, and gene expression analysis identified pathways associated with therapeutic effects. Results: The combination demonstrated dose-dependent effects, enhancing differentiation and reducing proliferation, cell viability, and colony-forming capacity. A synergistic effect was observed across AML cell lines. Gene expression profiling revealed the co-regulation of differentiation-associated genes, unveiling the mechanisms driving therapeutic synergy. Conclusion: Combination of CDK4/6 inhibitors with ATRA shows potential for differentiation-based AML treatment. This approach offers a promising avenue for improved outcomes in non-APL AML.
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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.
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Project description:To characterize the genes that are responsive or refractory to ATRA or ATO treatment in mouse APL cells
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Project description:This experiment aims at understanding the main transcriptomic basals differences between Pml+/+ and Pml-/- APL blasts and during ATRA+ATO treatment. Mice were transplanted were Pml+/+ or Pml-/- blasts. Once sick, mice were treated with 12 hours of ATRA+ATO therapy (ATRA: subcutaneous diffusion, ATO: intraperitoneal injection). After treatment, bone marrow cells were harvested and blasts were sorted (GFP blasts used). After sorting, cells were frozen at -80°C (in RNA lysis buffer). Then, RNA was extracted with the Qiagen RNeasy Minikit. Samples were then hybridized on MTA 1.0 chips.
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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.
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Project description:Purpose: Treatment of acute promyelocytic leukemia (APL) with the retinoid, all trans retinoic acid (ATRA), along with standard chemotherapy has significantly improved survival compared to chemotherapy alone1. ATRA mediates its benefit in APL by overcoming the transcriptional block mediated by PML-RAR-alpha fusion oncoprotein, thereby, restoring expression of retinoid response genes2. The therapeutic benefits observed with ATRA treatment in APL have not been achieved in the other more common sub-types of acute myeloblastic leukemia (AML)3. This likely reflects the recruitment of histone deacetylase complexes by other recurrent chromosomal translocations in AML cells4. In this experiment, we evaluated if treatment of the AML cell line, OCI/AML-2, with the histone deacetylase inhibitor, valproic acid (VPA), would alter the expression of sub-sets of genes by itself or in conjunction with ATRA that have been shown to be modulated by ATRA in APL2. Keywords: other
2005-05-17 | GSE2668 | GEO
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, FcRI, 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
Project description:Searching for new strategies of acute myeloid leukemia (AML) treatment is of particular interest. Cell lines, e. g. HL-60 and NB4, represent model systems to study molecular features of leukemic cells. The all-trans-retinoic acid (ATRA) has proven itself to be an effective treatment for one of AML subtypes, i.e., acute promyelocytic leukemia (APL). At the same time, ATRA causes granulocytic differentiation of non-APL leukemic cells in vitro. Combination of new therapeutics with ATRA could improve efficiency of treatment. Studying the proteome perturbation in leukemic cells under the ATRA treatment allows to determine potential regulatory molecules that could be affected pharmacologically. Thus, the TMT-based proteomic profiles of HL-60, NB4, and K562 cell lines under the ATRA treatment were obtained at 0, 3, 12, 24, and 72 h after the ATRA treatment.
2024-06-23 | PXD050317 | Pride
Project description:NB4 is an APL derived cell line, carrying the t(15;17) translocation and expressing the PML/RARa fusion protein. Still, an important question that remains to be addressed is whether PML/RARa target genes are transcriptionally suppressed in primary APL cells and re-activated in all-trans retinoic acid (ATRA) treated NB4 cells. Gene expression of NB4 cells treated with ATRA at different time points were analyzed.
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Project description:GTF2I-RARA is a newly identified RARA fusion gene in variant acute promyelocytic leukemia (APL) with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic PML-RARA in terms of therapeutic reaction. To reveal the functional characteristics and regulating mechanism of the GTF2I-RARA fusion gene, we established a GTF2I-RARA-transfected HL-60 cell model and confirmed its resistance to ATRA. Compared with PML-RARA, GTF2I-RARA has a higher affinity to HDAC3 under the treatment of ATRA. Using the ChIP-sequencing approach, we identified 221 GTF2I-RARA binding sites in model cells, and found that the RING finger protein 8(RNF8) is a target gene of GTF2I-RARA, which participated in the disease progression and therapy resistance in APL with GTF2I-RARA transcript. The elevated RNF8 expression promotes the interaction between RARA and RNF8 and induced RARA ubiquitylation and degradation, resulting in attenuated transcriptional activation of RARA. Our results suggested that RNF8 is a key GTF2I-RARA downstream event. Using the combination of MG132 and ATRA to treat the GTF2I-RARA-HL-60 cells, a synergistic effect leading to GTF2I-RARA-HL-60 cell differentiation was confirmed. Taken together, the targeting of RNF8 may be an alternative choice for treatment in variant APL with GTF2I-RARA fusion.
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