Palbociclib synergizes with ATRA to induce differentiation in AML
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ABSTRACT:
PROVIDER: PRJEB63304 | ENA |
REPOSITORIES: ENA
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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.
2024-12-01 | GSE190341 | GEO
Project description:It was reported that the CDK4/6 inhibitor, palbociclib, can enhance ATRA-induced myeloid differentiation in HL-60 cells. Therefore, in this study, the changes in mRNA expression patterns were precisely and comprehensively analyzed
2025-08-04 | GSE276457 | GEO
Project description:It was reported that the CDK4/6 inhibitor, palbociclib, can enhance ATRA-induced myeloid differentiation in HL-60 cells. Therefore, in this study, chromatin remodeling was precisely analyzed with a focus on histone H3.3 deposition.
2025-08-04 | GSE276456 | GEO
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.
2025-03-18 | GSE291868 | GEO
Project description:Proteome and phosphoproteome raw files from AML patient samples obtained before and after 3 and 8 days of ATRA/valproic acid treatment
2021-09-10 | PXD024197 | Pride
Project description:Preclinical studies have shown that combining the LSD1 inhibitor tranylcypromine (TCP) with all-trans retinoic acid (ATRA) induces differentiation and impairs survival in non-APL acute myeloid leukemia (AML). We conducted a Phase 1 clinical trial (NCT02273102) to evaluate the safety and preliminary activity of ATRA in combination with TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Seventeen patients (11 AML and 6 MDS) received ATRA-TCP therapy with ATRA (45 mg/m2 daily in divided doses) and TCP (3 dose levels: 10 mg twice-daily [BID], 20 mg BID, and 30 mg BID). ATRA-TCP had an acceptable safety profile. The maximum tolerated dose of TCP was 20 mg BID. There were 3 DLTs: dizziness (20 mg BID), asthenia (30 mg BID), and nausea/vomiting (30 mg BID). Best evaluable responses included 1 morphologic leukemia-free state (MLFS), 1 marrow complete remission (CR) with hematologic improvement, 2 stable disease with hematologic improvement, and 2 stable disease. In 13 response-evaluable patients, the overall response rate was 30.8% and clinical benefit rate 46.2%. Gene expression profiling of patient blasts showed that responding patients had a more dormant phenotype compared to non-responders at baseline. In human AML cell lines, we showed that treatment with ATRA-TCP increases differentiation capacity and/or cell death, and that ATRA-TCP regulates the in vitro expression of genes that segregate primary patients by their clinical response. These data indicate that LSD1 inhibition sensitizes AML cells to ATRA-induced differentiation and cell death and may restore clinical responsiveness in subsets of MDS and AML patients.
2021-06-21 | GSE151594 | GEO
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: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:Transcriptome analysis in HL-60 cells after combined treatment with ATRA and palbociclib
| PRJNA1157416 | ENA
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