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2000
Volume 20, Issue 2
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Chromosomal rearrangements involving the Mixed lineage leukemia (MLL) gene are observed in acute leukemia (AL) patients, which have poor prognosis, especially in infants. Hence, there is still a challenge to develop other effective agents to treat AL with MLL rearrangements (MLLr). MLL has been shown to rearrange with partner genes, of which the most frequently observed are AF4 and AF9. Moreover, AL is characterized by a differentiation blockage resulting in the accumulation of immature cells. An ent-kaurene diterpenoid compound, Jiyuan Oridonin A (JOA), has been shown to reduce the viability of AML cells by differentiation.

Methods

We aimed to evaluate the effect of JOA on the growth and differentiation of AL cells (SEM, JURKAT and MV4-11) including cells with MLLr-AF4 by cell proliferation assay, colony formation assay, cell cycle analysis, cell apoptosis analysis, measurement of cell surface antigens and cell morphology, mRNA-sequencing analysis, quantitative Real-time PCR and Western blotting analysis.

Results

Our findings demonstrated that the proliferation of AL cells including cells with MLLr-AF4 was significantly suppressed by JOA, which induced cell differentiation followed by G0/G1 cell cycle withdrawal. Moreover, JOA-mediated cell differentiation was likely due to activation of G-CSFR in MV4-11 cells.

Conclusion

Our results suggest that JOA may be considered a promising anti-leukemia compound to develop to surmount the differentiation block in AL patients.

© 2025 Bentham Science Publishers
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2025-07-23

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References

  1. Soto-MercadoV. Mendivil-PerezM. Jimenez-Del-RioM. FoxJ.E. Velez-PardoC. Cannabinoid CP55940 selectively induces apoptosis in Jurkat cells and in ex vivo T-cell acute lymphoblastic leukemia through H2O2 signaling mechanism.Leuk. Res.20209510638910.1016/j.leukres.2020.106389 32540572
     [Google Scholar]
  2. LinS. PtasinskaA. AssiS.A. The transcriptome heterogeneity of mll-fusion all is driven by fusion partners via distinct chromatin binding.Blood20161282257610.1182/blood.V128.22.576.576
     [Google Scholar]
  3. LiC. WrightS. HuJ. ZhangY. HyleJ. LuR. Interrogating novel bromodomain inhibition resistance mechanism in mllr leukemia.Blood2021138Suppl. 12610.1182/blood‑2021‑147003
     [Google Scholar]
  4. DaigleS.R. OlhavaE.J. TherkelsenC.A. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.Blood201312261017102510.1182/blood‑2013‑04‑497644 23801631
     [Google Scholar]
  5. TamaiH. YamaguchiH. HamaguchiH. Clinical features of adult acute leukemia with 11q23 abnormalities in Japan: A co-operative multicenter study.Int. J. Hematol.200887219520210.1007/s12185‑008‑0034‑2 18253706
     [Google Scholar]
  6. ŚniegockaM. LiccardoF. FaziF. MasciarelliS. Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia.Drug Resist. Updat.20226410085310.1016/j.drup.2022.100853 35870226
     [Google Scholar]
  7. LongL. AssarafY.G. LeiZ.N. Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia.Drug Resist. Updat.20205210070310.1016/j.drup.2020.100703 32599434
     [Google Scholar]
  8. KossC. NanceS. ConnellyM. Targeted inhibition of the MLL transcriptional complex by proteosome inhibitors elicits a high response rate in relapsed/refractory mll rearranged leukemia.Blood20141242197210.1182/blood.V124.21.972.972
     [Google Scholar]
  9. BizzarriM. GiulianiA. CucinaA. MininiM. Redifferentiation therapeutic strategies in cancer.Drug Discov. Today202025473173810.1016/j.drudis.2020.01.021 32027971
     [Google Scholar]
  10. YaoJ. LiG. CuiZ. The Histone deacetylase inhibitor i1 induces differentiation of acute leukemia cells with mll gene rearrangements via epigenetic modification.Front. Pharmacol.20221387607610.3389/fphar.2022.876076 35571127
     [Google Scholar]
  11. KeY. LiangJ.J. HouR.J. Synthesis and biological evaluation of novel Jiyuan Oridonin A-1,2,3-triazole-azole derivatives as antiproliferative agents.Eur. J. Med. Chem.20181571249126310.1016/j.ejmech.2018.08.056 30193221
     [Google Scholar]
  12. LiuH.M. ZhuW.C. ZhuC.G. Novel entkaurene diterpene compound and its derivatives, their preparation and their use.U.S. Patent 80844302011
  13. QuM. DuanY. ZhaoM. Jiyuan oridonin A overcomes differentiation blockade in acute myeloid leukemia cells with MLL rearrangements via multiple signaling pathways.Front. Oncol.20211165972010.3389/fonc.2021.659720 33842376
     [Google Scholar]
  14. LiF. GaoC. LiX. Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells.Front. Pharmacol.202213100155210.3389/fphar.2022.1001552 36133825
     [Google Scholar]
  15. MaX. ZhaoM. WuZ.X. The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells.Front. Oncol.20221285557010.3389/fonc.2022.855570 35494054
     [Google Scholar]
  16. HuK. LiaoD. WuW. Targeting the anaphase-promoting complex/cyclosome (APC/C)- bromodomain containing 7 (BRD7) pathway for human osteosarcoma.Oncotarget20145103088310010.18632/oncotarget.1816 24840027
     [Google Scholar]
  17. FujitaS. HonmaD. AdachiN. Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia.Leukemia201832485586410.1038/leu.2017.300 28951561
     [Google Scholar]
  18. ChattertonZ. MorenosL. SafferyR. CraigJ.M. AshleyD. WongN.C. DNA methylation and miRNA expression profiling in childhood B-cell acute lymphoblastic leukemia.Epigenomics20102569770810.2217/epi.10.39 22122053
     [Google Scholar]
  19. CortesJ.E. KantarjianH.M. Acute lymphoblastic leukemia a comprehensive review with emphasis on biology and therapy.Cancer199576122393241710.1002/1097‑0142(19951215)76:12<2393:AID‑CNCR2820761203>3.0.CO;2‑P 8625065
     [Google Scholar]
  20. ErfurthF. HemenwayC.S. de ErkenezA.C. DomerP.H. MLL fusion partners AF4 and AF9 interact at subnuclear foci.Leukemia20041819210210.1038/sj.leu.2403200 14603337
     [Google Scholar]
  21. MarksD.I. MoormanA.V. ChiltonL. The clinical characteristics, therapy and outcome of 85 adults with acute lymphoblastic leukemia and t(4;11)(q21;q23)/MLL-AFF1 prospectively treated in the UKALLXII/ECOG2993 trial.Haematologica201398694595210.3324/haematol.2012.081877 23349309
     [Google Scholar]
  22. PuiC.H. GaynonP.S. BoyettJ.M. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.Lancet200235993211909191510.1016/S0140‑6736(02)08782‑2 12057554
     [Google Scholar]
  23. MannG. AttarbaschiA. SchrappeM. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)–rearranged acute lymphoblastic leukemia: Results from the Interfant-99 Study.Blood2010116152644265010.1182/blood‑2010‑03‑273532 20592248
     [Google Scholar]
  24. BarberN. BelovL. ChristophersonR.I. All-trans retinoic acid induces different immunophenotypic changes on human HL60 and NB4 myeloid leukaemias.Leuk. Res.200832231532210.1016/j.leukres.2007.04.013 17561254
     [Google Scholar]
  25. LochabS. PalP. KapoorI. E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation.Biochim. Biophys. Acta Mol. Cell Res.20131833122639265210.1016/j.bbamcr.2013.06.018 23820376
     [Google Scholar]
  26. ZhuQ.S. RobinsonL.J. RoginskayaV. CoreyS.J. G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses.Blood200410393305331210.1182/blood‑2003‑06‑1861 14656892
     [Google Scholar]
  27. FukunagaR. Ishizaka-IkedaE. NagataS. Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony-stimulating factor receptor.Cell19937461079108710.1016/0092‑8674(93)90729‑A 7691413
     [Google Scholar]
  28. HassR. GunjiH. DattaR. Differentiation and retrodifferentiation of human myeloid leukemia cells is associated with reversible induction of cell cycle-regulatory genes.Cancer Res.199252614451450 1531783
     [Google Scholar]
  29. KreisN.N. LouwenF. YuanJ. The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy.Cancers2019119122010.3390/cancers11091220 31438587
     [Google Scholar]
  30. BiG. LiangJ. ZhaoM. miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways.Mol. Ther. Nucleic Acids20222836638610.1016/j.omtn.2022.03.020 35505963
     [Google Scholar]
  31. AbbasT. DuttaA. p21 in cancer: Intricate networks and multiple activities.Nat. Rev. Cancer20099640041410.1038/nrc2657 19440234
     [Google Scholar]
  32. CarreiraS. GoodallJ. AksanI. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression.Nature2005433702776476910.1038/nature03269 15716956
     [Google Scholar]
  33. SchwentnerR. Bennani-BaitiI. KovarH. CDKN1A gene regulation in Ewing’s sarcoma.Cancer Res.200969Suppl. 91536
     [Google Scholar]
  34. LuoJ. LiuK. YaoY. DMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell.Cancer Lett.2019453455610.1016/j.canlet.2019.03.045 30928384
     [Google Scholar]
  35. CazierJ.B. RaoS.R. McLeanC.M. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.Nat. Commun.201451375610.1038/ncomms4756 24777035
     [Google Scholar]
/content/journals/pra/10.2174/0115748928263141231204112640
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Differentiation of Acute Leukemia Cells Including Cells with MLL-AF4 Rearrangements Induced by Jiyuan Oridonin A
Recent Patents on Anti-Cancer Drug Discovery 20, 158 (2025); https://doi.org/10.2174/0115748928263141231204112640
/content/journals/pra/10.2174/0115748928263141231204112640
/content/journals/pra/10.2174/0115748928263141231204112640
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  • Article Type:     Research Article
Keyword(s): Acute leukemia; acute myeloid leukemia (AML); AF4; differentiation blockage; Jiyuan Oridonin A; mixed lineage leukemia rearrangements

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