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Chinese Medicine Regulates DNA Methylation to Treat Haematological Malignancies: A New Paradigm of “State-Target Medicine”

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Abstract

Aberrant regulation of DNA methylation plays a crucial causative role in haematological malignancies (HMs). Targeted therapy, aiming for DNA methylation, is an effective mainstay of modern medicine; however, many issues remain to be addressed. The progress of epigenetic studies and the proposed theory of “state-target medicine” have provided conditions to form a new treatment paradigm that combines the “body state adjustment” of CM with targeted therapy. We discussed the correlation between Chinese medicine (CM) syndromes/states and DNA methylation in this paper. Additionally, the latest research findings on the intervention and regulation of DNA methylation in HMs, including the core targets, therapy status, CM compounds and active components of the Chinese materia medica were concisely summarized to establish a theoretical foundation of “state-target synchronous conditioning” pattern of integrative medicine for HMs, simultaneously leading a new perspective in clinical diagnosis and therapy.

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References

  1. Navada SC, Steinmann J, Lübbert M, Silverman LR. Clinical development of demethylating agents in hematology. J Clin Invest 2014;124:40–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tong XL. State target medicine: the future development of Chinese medicine. Chin J Integr Trad West Med (Chin) 2021;41:16–18.

    Google Scholar 

  3. Schulz VP, Yan H, Lezon-Geyda K, An X, Hale J, Hillyer CD, et al. A unique epigenomic landscape defines human erythropoiesis. Cell Rep 2019;28:2996–3009.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lessard S, Beaudoin M, Benkirane K, Lettre G. Comparison of DNA methylation profiles in human fetal and adult red blood cell progenitors. Genome Med 2015;7:1–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Hogart A, Lichtenberg J, Ajay SS, Anderson S, Margulies EH, Bodine DM. Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites. Genome Res 2012;22:1407–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tu PS, Lin EC, Chen HW, Chen SW, Lin TA, Gau JP, et al. The extracellular signal-regulated kinase 1/2 modulates the intracellular localization of DNA methyltransferase 3A to regulate erythrocytic differentiation. Am J Transl Res 2020;12:1016–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang TJ, Zhang LC, Xu ZJ, Zhou JD. Expression and prognosis analysis of DNMT family in acute myeloid leukemia. Aging (Albany NY) 2020;12:14677–14690.

    Article  CAS  Google Scholar 

  8. Anteneh H, Fang J, Song J. Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. Nat Commun 2020;11:2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R, et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 2014;25:442–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nguyen TV, Yao S, Wang Y, Rolfe A, Selvaraj A, Darman R, et al. The R882H DNMT3A hot spot mutation stabilizes the formation of large DNMT3A oligomers with low DNA methyltransferase activity. J Biol Chem 2019;294:16966–16977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Khrabrova DA, Loiko AG, Tolkacheva AA, Cherepanova NA, Zvereva MI, Kirsanova OV, et al. Functional analysis of DNMT3A DNA methyltransferase mutations reported in patients with acute myeloid leukemia. Biomolecules 2020;10:8.

    Article  CAS  Google Scholar 

  12. Sandoval JE, Huang YH, Muise A, Goodell MA, Reich NO. Mutations in the DNMT3A DNA methyltransferase in acute myeloid leukemia patients cause both loss and gain of function and differential regulation by protein partners. J Biol Chem 2019;294:4898–4910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Haney SL, Upchurch GM, Opavska J, Klinkebiel D, Hlady RA, Suresh A, et al. Promoter hypomethylation and expression is conserved in mouse chronic lymphocytic leukemia induced by decreased or inactivated DNMT3a. Cell Rep 2016;15:1190–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoang NM, Rui L. DNA methyltransferases in hematological malignancies. J Genet Genomics 2020;47:361–372.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Rau RE, Rodriguez BA, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood 2016;128:971–981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bledea R, Vasudevaraja V, Patel S, Stafford J, Serrano J, Esposito G, et al. Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers. Sci Rep 2019;9:16830.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gu Y, Yang R, Yang Y, Zhao Y, Wakeham A, Li WY, et al. IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis. Blood 2021;137:945–958.

    Article  CAS  PubMed  Google Scholar 

  18. Glass JL, Hassane D, Wouters BJ, Kunimoto H, Avellino R, Garrett-Bakelman FE, et al. Epigenetic identity in AML depends on disruption of nonpromoter regulatory elements and is affected by antagonistic effects of mutations in epigenetic modifiers. Cancer Discovery 2017;7:868–883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016;374:2209–2221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 2011;473:398–402.

    Article  CAS  PubMed  Google Scholar 

  21. Inokura K, Fujiwara T, Saito K, Iino T, Hatta S, Okitsu Y, et al. Impact of TET2 deficiency on iron metabolism in erythroblasts. Exp Hematol 2017;49:56–67.e5.

    Article  CAS  PubMed  Google Scholar 

  22. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, et al. Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A 2011;108:14566–14571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 2011;20:25–38.

    Article  CAS  PubMed  Google Scholar 

  24. Bowman RL, Levine RL. TET2 in normal and malignant hematopoiesis. Cold Spring Harb Perspect Med 2017;7:a026518.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Poole CJ, Lodh A, Choi JH, van Riggelen J. MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy) methylation and gene expression to maintain a neoplastic phenotype in T-ALL. Epigenetics Chromatin 2019;12:41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Blecua P, Martinez-Verbo L, Esteller M. The DNA methylation landscape of hematological malignancies: an update. Mol Oncol 2020;14:1616–1639.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dimopoulos K, Grønbaek K. Epigenetic therapy in hematological cancers. APMIS 2019;127:316–328.

    Article  PubMed  Google Scholar 

  28. Bates SE. Epigenetic therapies for cancer. N Engl J Med 2020;383:650–663.

    Article  CAS  PubMed  Google Scholar 

  29. Gou X, Gao Z, Yang Y, Li Q, Chen K, Lei Y, et al. Statetarget strategy: a bridge for the integration of Chinese and Western medicine. J Tradit Chin Med 2021;41:1–5.

    PubMed  Google Scholar 

  30. Kelly AD, Kroeger H, Yamazaki J, Taby R, Neumann F, Yu S, et al. A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favourable outcome. Leukemia 2017;31:2011–2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang J, Li F, Ma Z, Yu M, Guo Q, Huang J, et al. High expression of TET1 predicts poor survival in cytogenetically normal acute myeloid leukemia from two cohorts. EBioMedicine 2018;28:90–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zeng YQ, Li WH, Zhang TE, Tan XJ, Qin J, Cui JM, et al. Study on the regulatory mechanism of immune-related gene CPG island in Kidney-yang deficiency syndrome. Lishizhen Med Mater Med Res (Chin) 2013;24:1515–1517.

    CAS  Google Scholar 

  33. Yao H, Mo S, Wang J, Li Y, Wang CZ, Wan JY, et al. Genome-wide DNA methylation profiles of phlegm-dampness constitution. Cell Physiol Biochem 2018;45:1999–2008.

    Article  CAS  PubMed  Google Scholar 

  34. Liu F, Xu RR. Study on the correlation between Chinese medical syndrome types and ID4 gene promoter methylation in human acute myeloid leukemia. Chin J Integr Tradit West Med (Chin) 2012;32:471–473.

    CAS  Google Scholar 

  35. Hu XQ, Su SB. An overview of epigenetics in Chinese medicine researches. Chin J Integr Med 2017;23:714–720.

    Article  PubMed  Google Scholar 

  36. Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, et al. Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet 2019;10:1–16.

    Article  CAS  Google Scholar 

  37. Martín I, Navarro B, Solano C, Calabuig M, Hernández-Boluda JC, Amat P, et al. Synergistic antioncogenic activity of azacitidine and curcumin in myeloid leukemia cell lines and patient samples. Anticancer Res 2019;39:4757–4766.

    Article  PubMed  CAS  Google Scholar 

  38. Kedhari Sundaram M, Hussain A, Haque S, Raina R, Afroze N. Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J Cell Biochem 2019;120:18357–18369.

    Article  CAS  PubMed  Google Scholar 

  39. Qing Y, Hu H, Liu Y, Feng T, Meng W, Jiang L, et al. Berberine induces apoptosis in human multiple myeloma cell line U266 through hypomethylation of p53 promoter. Cell Biol Int 2014;38:563–570.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang RJ, Ma LM, Lu YJ, Bai B. Triptolide affect the methylation status of HL-60 cells. Chin J Hematol (Chin) 2014;35:443–447.

    CAS  Google Scholar 

  41. Lee WY, Chen KC, Chen HY, Chen CY. Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers. Biomed Res Int 2014;2014:364625.

    PubMed  PubMed Central  Google Scholar 

  42. Wang LP, Zhao YN, Sun X, Gao RL. Effects of bufalin on up-regulating methylation of Wilm’s tumor 1 gene in human erythroid leukemic cells. Chin J Integr Med 2017;23:288–294.

    Article  CAS  PubMed  Google Scholar 

  43. Wang LP, Zhao YN, Gao RL. Resveratrol can reduce the expression of WT1 by methylation in K562 cells. Chin J Hematol (Chin) 2014;35:245–246.

    Google Scholar 

  44. Wang LP. The study of low-polarity ginsenoside ALK in regulating the methylation of WT1 gene in erythroleukemia cells in vivo and in vitro [Dissertation]. Hangzhou: Zhejiang Chinese Medical University; 2015.

    Google Scholar 

  45. Zhou QB, Yang XH, Wang HZ, Wang DX, Xu YG, Hu XM, et al. Effect of Qinghuang Powder combined with Bupi Yishen Decoction in treating patients with refractory cytopenia with multilineage dysplasia through regulating DNA methylation. Chin J Integr Med 2019;25:354–359.

    Article  PubMed  Google Scholar 

  46. Zhou QB, Zhu QZ, Wang HZ, Wang DX, Liu ZT, Xu YG, et al. Traditional Chinese medicine containing arsenic treated MDS patients effectively through regulating aberrant hypomethylation. Evid Based Complement Alternat Med 2020;2020:7469809.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Shen XH, Sun WL, Bao JZ, Hu MH, Wang J, Hu LY, et al. Clinical observation of “Jianpi Bushen Jiedu Recipe” in treating myelodysplastic syndrome. Acad J Shanghai Univ Tradit Chin Med (Chin) 2012;26:34–37.

    Google Scholar 

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Authors and Affiliations

Authors

Contributions

Gao RL and Shen FL conceived, designed, collected the data and wrote the manuscript. Zhao YN consulted relevant literatures and clinical guidelines. Yu XL, Wang BL, Wu XL and Lan GC participated in searching and reading the literatures.

Corresponding author

Correspondence to Rui-lan Gao.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Supported by the National Natural Science Foundation of China (No. 81774068), the Natural Science Foundation of Zhejiang Province (No. LY20H290004), Youth Project of the Natural Science Foundation of Zhejiang Province (No. LQ19H290002)

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Shen, Fl., Zhao, Yn., Yu, Xl. et al. Chinese Medicine Regulates DNA Methylation to Treat Haematological Malignancies: A New Paradigm of “State-Target Medicine”. Chin. J. Integr. Med. 28, 560–566 (2022). https://doi.org/10.1007/s11655-021-3316-7

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