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MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases

  • Authors:
    • Zhuanzhen Zheng
    • Xiuhua Chen
    • Yaofang Zhang
    • Fanggang Ren
    • Yanping Ma
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    Affiliations: Department of Hematopathology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
    Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 140
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    Published online on: November 3, 2023
       https://doi.org/10.3892/ijo.2023.5588
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Abstract

The transformation of myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) poses a significant clinical challenge. The trimethylation of H3 on lysine 27 (H3K27me3) methylase and de‑methylase pathway is involved in the regulation of MDS progression. The present study investigated the functional mechanisms of the MEK/ERK and PI3K/AKT pathways in the MDS‑to‑AML transformation. MDS‑AML mouse and SKM‑1 cell models were first established and this was followed by treatment with the MEK/ERK pathway inhibitor, U0126, the PI3K/AKT pathway inhibitor, Ly294002, or their combination. H3K27me3 methylase, enhancer of zeste homolog (EZH)1, EZH2, demethylase Jumonji domain‑containing protein‑3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) and H3K27me3 protein levels were determined using western blot analysis. Cell viability, cycle distribution and proliferation were assessed using CCK‑8, flow cytometry, EdU and colony formation assays. The ERK and AKT phosphorylation levels in clinical samples and established models were determined, and SKM‑1 cell behaviors were assessed. The levels of H3K27me3 methylases and de‑methylases and distal‑less homeobox 5 (DLX5) were measured. The results revealed that the ERK and AKT phosphorylation levels were elevated in patients with MDS and MDS‑AML, and in mouse models. Treatment with U0126, a MEK/ERK pathway inhibitor, and Ly294002, a PI3K/AKT pathway inhibitor, effectively suppressed ERK and AKT phosphorylation in mice with MDS‑AML. It was observed that mice with MDS treated with U0126/Ly294002 exhibited reduced transformation to AML, delayed disease transformation and increased survival rates. Treatment of the SKM‑1 cells with U0126/Ly294002 led to a decrease in cell viability and proliferation, and to an increase in cell cycle arrest by suppressing ERK/PI3K phosphorylation. Moreover, treatment with U0126/Ly294002 downregulated EZH2/EZH1 expression, and upregulated JMJD3/UTX expression. The effects of U0126/Ly294002 were nullified when EZH2/EZH1 was overexpressed or when JMJD3/UTX was inhibited in the SKM‑1 cells. Treatment with U0126/Ly294002 also resulted in a decreased H3K27me3 protein level and H3K27me3 level in the DLX5 promoter region, leading to an increased DLX5 expression. Overall, the findings of the present study suggest that U0126/Ly294002 participates in MDS‑AML transformation by modulating the levels of H3K27me3 methylases and de‑methylases, and regulating DLX5 transcription and expression.
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1 

Hasserjian RP: Myelodysplastic syndrome updated. Pathobiology. 86:7–13. 2019.

2 

Haferlach T: The molecular pathology of myelodysplastic syndrome. Pathobiology. 86:24–29. 2019.

3 

Yan X, Lai B, Zhou X, Yang S, Ge Q, Zhou M, Shi C, Xu Z and Ouyang G: The differential expression of CD47 may be related to the pathogenesis from myelodysplastic syndromes to acute myeloid leukemia. Front Oncol. 12:8729992022.

4 

Menssen AJ and Walter MJ: Genetics of progression from MDS to secondary leukemia. Blood. 136:50–60. 2020.

5 

Rankin EB, Narla A, Park JK, Lin S and Sakamoto KM: Biology of the bone marrow microenvironment and myelodysplastic syndromes. Mol Genet Metab. 116:24–28. 2015.

6 

Liu W, Teodorescu P, Halene S and Ghiaur G: The coming of age of preclinical models of MDS. Front Oncol. 12:8150372022.

7 

Venney D, Mohd-Sarip A and Mills KI: The impact of epigenetic modifications in myeloid malignancies. Int J Mol Sci. 22:50132021.

8 

Shukron O, Vainstein V, Kündgen A, Germing U and Agur Z: Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database. Am J Hematol. 87:853–860. 2012.

9 

Zhang Z, Richmond A and Yan C: Immunomodulatory properties of PI3K/AKT/mTOR and MAPK/MEK/ERK inhibition augment response to immune checkpoint blockade in melanoma and triple-negative breast cancer. Int J Mol Sci. 23:73532022.

10 

Fu NJ, Xi RY, Shi XK, Li RZ, Zhang ZH, Li LY, Zhang GL and Wang F: Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways. Toxicol Appl Pharmacol. 441:1159882022.

11 

Peng M, Fan S, Li J, Zhou X, Liao Q, Tang F and Liu W: Programmed death-ligand 1 signaling and expression are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in tongue squamous cell carcinoma. Genes Nutr. 17:32022.

12 

Zebisch A, Czernilofsky AP, Keri G, Smigelskaite J, Sill H and Troppmair J: Signaling through RAS-RAF-MEK-ERK: From basics to bedside. Curr Med Chem. 14:601–623. 2007.

13 

Liang S, Zhou X, Cai D, Rodrigues-Lima F, Chi J and Wang L: Network pharmacology and experimental validation reveal the effects of chidamide combined with aspirin on acute myeloid leukemia-myelodysplastic syndrome cells through PI3K/AKT pathway. Front Cell Dev Biol. 9:6859542021.

14 

Akutagawa J, Hua ng TQ, Epstein I, Chang T, Quirindongo-Crespo M, Cottonham CL, Dail M, Slusher BS, Friedman LS, Sampath D and Braun BS: Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras. Leukemia. 30:1335–1343. 2016.

15 

Chung E, Hsu CL and Kondo M: Constitutive MAP kinase activation in hematopoietic stem cells induces a myeloproliferative disorder. PLoS One. 6:e283502011.

16 

Gonzalez-Lugo JD, Chakraborty S, Verma A and Shastri A: The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia. Semin Hematol. 58:56–65. 2021.

17 

Hojfeldt JW, Agger K and Helin K: Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 12:917–930. 2013.

18 

Ruan XF, Li YJ, Ju CW, Shen Y, Lei W, Chen C, Li Y, Yu H, Liu YT, Kim IM, et al: Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. Acta Pharmacol Sin. 39:579–586. 2018.

19 

Rizk M, Rizq O, Oshima M, Nakajima-Takagi Y, Koide S, Saraya A, Isshiki Y, Chiba T, Yamazaki S, Ma A, et al: Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma. Cancer Sci. 110:3695–3707. 2019.

20 

Ferraro A, Mourtzoukou D, Kosmidou V, Avlonitis S, Kontogeorgos G, Zografos G and Pintzas A: EZH2 is regulated by ERK/AKT and targets integrin alpha2 gene to control epithelial-mesenchymal transition and anoikis in colon cancer cells. Int J Biochem Cell Biol. 45:243–254. 2013.

21 

Zhang TJ, Xu ZJ, Gu Y, Wen XM, Ma JC, Zhang W, Deng ZQ, Leng JY, Qian J, Lin J and Zhou JD: Identification and validation of prognosis-related DLX5 methylation as an epigenetic driver in myeloid neoplasms. Clin Transl Med. 10:e292020.

22 

Zheng Z, Li L, Li G, Zhang Y, Dong C, Ren F, Chen W and Ma Y: EZH2/EHMT2 histone methyltransferases inhibit the transcription of DLX5 and promote the transformation of myelodysplastic syndrome to acute myeloid leukemia. Front Cell Dev Biol. 9:6197952021.

23 

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M and Vardiman JW: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127:2391–2405. 2016.

24 

You Y, Niu Y, Zhang J, Huang S, Ding P, Sun F and Wang X: U0126: Not only a MAPK kinase inhibitor. Front Pharmacol. 13:9270832022.

25 

Xu CN, Kong LH, Ding P, Liu Y, Fan ZG, Gao EH, Yang J and Yang LF: Melatonin ameliorates pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway. Biochim Biophys Acta Mol Basis Dis. 1866:1658482020.

26 

Guirguis AA, Slape CI, Failla LM, Saw J, Tremblay CS, Powell DR, Rossello F, Wei A, Strasser A and Curtis DJ: PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia. Cell Death Differ. 23:1049–1059. 2016.

27 

Estey E, Hasserjian RP and Döhner H: Distinguishing AML from MDS: A fixed blast percentage may no longer be optimal. Blood. 139:323–332. 2022.

28 

Zatroch KK, Knight CG, Reimer JN and Pang DS: Refinement of intraperitoneal injection of sodium pentobarbital for euthanasia in laboratory rats (Rattus norvegicus). BMC Vet Res. 13:602017.

29 

Geng Y, Wu W, Zhou L, Li J, Geng Y and Yang Y: Synergistic effects of LY294002 and ABT199 on the cell cycle in K562, HL60 and KG1a cells. Oncol Rep. 45:972021.

30 

Wang C, Wang K, Li SF, Song SJ, Du Y, Niu RW, Qian XW, Peng XQ and Chen FH: 4-Amino-2-trifluoromethyl-phenyl retinate induced differentiation of human myelodysplastic syndromes SKM-1 cell lines by up-regulating DDX23. Biomed Pharmacother. 123:1097362020.

31 

Zhou W, Xu S, Ying Y, Zhou R and Chen X: Resveratrol suppresses growth and migration of myelodysplastic cells by inhibiting the expression of elevated cyclin D1 (CCND1). DNA Cell Biol. 36:966–975. 2017.

32 

Dagdemir A, Durif J, Ngollo M, Bignon YJ and Bernard-Gallon D: Histone lysine trimethylation or acetylation can be modulated by phytoestrogen, estrogen or anti-HDAC in breast cancer cell lines. Epigenomics. 5:51–63. 2013.

33 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.

34 

Trivedi G, Inoue D and Zhang L: Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies. Trends Mol Med. 27:990–999. 2021.

35 

Yue Y, Wang Y, He Y, Yang S, Chen Z, Wang Y, Xing S, Shen C, Amin HM, Wu D and Song YH: Reversal of bortezomib resistance in myelodysplastic syndrome cells by MAPK inhibitors. PLoS One. 9:e909922014.

36 

Yin J, Li X, Zhang Z, Luo X, Wang L and Liu L: SPAG6 silencing induces apoptosis in the myelodysplastic syndrome cell line SKM-1 via the PTEN/PI3K/AKT signaling pathway in vitro and in vivo. Int J Oncol. 53:297–306. 2018.

37 

Lee P, Yim R, Yung Y, Chu HT, Yip PK and Gill H: Molecular targeted therapy and immunotherapy for myelodysplastic syndrome. Int J Mol Sci. 22:102322021.

38 

Wheeler EC, Vora S, Mayer D, Kotini AG, Olszewska M, Park SS, Guccione E, Teruya-Feldstein J, Silverman L, Sunahara RK, et al: Integrative RNA-omics discovers GNAS alternative splicing as a phenotypic driver of splicing factor-mutant neoplasms. Cancer Discov. 12:836–855. 2022.

39 

Lin S, Li J, Zhou W, Qian W, Wang B and Chen Z: BIIB021, an Hsp90 inhibitor, effectively kills a myelodysplastic syndrome cell line via the activation of caspases and inhibition of PI3K/Akt and NF-κB pathway proteins. Exp Ther Med. 7:1539–1544. 2014.

40 

Lin YW, Slape C, Zhang Z and Aplan PD: NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood. 106:287–295. 2005.

41 

Maiti A, Naqvi K, Kadia TM, Borthakur G, Takahashi K, Bose P, Daver NG, Patel A, Alvarado Y, Ohanian M, et al: Phase II trial of MEK inhibitor binimetinib (MEK162) in RAS-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 19:142–148.e1. 2019.

42 

Ricciardi MR, Scerpa MC, Bergamo P, Ciuffreda L, Petrucci MT, Chiaretti S, Tavolaro S, Mascolo MG, Abrams SL, Steelman LS, et al: Therapeutic potential of MEK inhibition in acute myelogenous leukemia: Rationale for 'vertical' and 'lateral' combination strategies. J Mol Med (Berl). 90:1133–1144. 2012.

43 

Ragon BK, Odenike O, Baer MR, Stock W, Borthakur G, Patel K, Han L, Chen H, Ma H, Joseph L, et al: Oral MEK 1/2 inhibitor trametinib in combination with AKT inhibitor GSK2141795 in patients with acute myeloid leukemia with RAS mutations: A phase II study. Clin Lymphoma Myeloma Leuk. 19:431–440.e13. 2019.

44 

Täger M, Horn S, Latuske E, Ehm P, Schaks M, Nalaskowski M, Fehse B, Fiedler W, Stocking C, Wellbrock J and Jücker M: SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model. Gene Ther. 24:749–753. 2017.

45 

Lin L, Que Y, Lu P, Li H, Xiao M, Zhu X and Li D: Chidamide inhibits acute myeloid leukemia cell proliferation by lncRNA VPS9D1-AS1 downregulation via MEK/ERK signaling pathway. Front Pharmacol. 11:5696512020.

46 

Riquelme E, Behrens C, Lin HY, Simon G, Papadimitrakopoulou V, Izzo J, Moran C, Kalhor N, Lee JJ, Minna JD and Wistuba II: Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations. Cancer Res. 76:675–685. 2016.

47 

Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, Katano H, Hishima T, Kobayashi S, Nakano K, et al: Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep. 29:2321–2337.e7. 2019.

48 

Rejlova K, Musilova A, Kramarzova KS, Zaliova M, Fiser K, Alberich-Jorda M, Trka J and Starkova J: Low HOX gene expression in PML-RARα-positive leukemia results from suppressed histone demethylation. Epigenetics. 13:73–84. 2018.

49 

Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE and Helin K: UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 449:731–734. 2007.

50 

Zheng L, Zhai Y, Li N, Ma F, Zhu H, Du X, Li G and Hua J: The modification of Tet1 in male germline stem cells and interact with PCNA, HDAC1 to promote their self-renewal and proliferation. Sci Rep. 6:374142016.

51 

Kosalai ST, Morsy MHA, Papakonstantinou N, Mansouri L, Stavroyianni N, Kanduri C, Stamatopoulos K, Rosenquist R and Kanduri M: EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia. Epigenetics. 14:1125–1140. 2019.

52 

Zitzmann K, Rüden J, Brand S, Göke B, Lichtl J, Spöttl G and Auernhammer CJ: Compensatory activation of Akt in response to mTOR and Raf inhibitors-a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Lett. 295:100–109. 2010.

53 

Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM and Engelman JA: MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 72:3228–3237. 2012.

54 

Wu YL, Maachani UB, Schweitzer M, Singh R, Wang M, Chang R and Souweidane MM: Dual inhibition of PI3K/AKT and MEK/ERK pathways induces synergistic antitumor effects in diffuse intrinsic pontine glioma cells. Transl Oncol. 10:221–228. 2017.

55 

Cao Z, Liao Q, Su M, Huang K, Jin J and Cao D: AKT and ERK dual inhibitors: The way forward? Cancer Lett. 459:30–40. 2019.

56 

Ramakrishnan V, Kimlinger T, Haug J, Painuly U, Wellik L, Halling T, Rajkumar SV and Kumar S: Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway. PLoS One. 7:e500052012.

57 

Liu L, Chen J, Cao M, Wang J and Wang S: NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells. Cancer Chemother Pharmacol. 84:1303–1314. 2019.

58 

Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y, Zhang Z, He Q and Chang C: Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: Relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol. 90:643–653. 2011.

59 

Yu SH, Zhu KY, Chen J, Liu XZ, Xu PF, Zhang W, Yan L, Guo HZ and Zhu J: JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 9:33692018.

60 

Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, Wang C and Iwama A: Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood. 126:1172–1183. 2015.

61 

Wu B, Pan X, Chen X, Chen M, Shi K, Xu J, Zheng J, Niu T, Chen C, Shuai X and Liu Y: Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy. Signal Transduct Target Ther. 4:112019.

62 

Fujii S, Tokita K, Wada N, Ito K, Yamauchi C, Ito Y and Ochiai A: MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene. 30:4118–4128. 2011.

63 

Jiang Q, Huang X, Hu X, Shan Z, Wu Y, Wu G and Lei L: Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways. Stem Cells. 38:960–972. 2020.

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Zheng Z, Chen X, Zhang Y, Ren F and Ma Y: MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases. Int J Oncol 63: 140, 2023.
APA
Zheng, Z., Chen, X., Zhang, Y., Ren, F., & Ma, Y. (2023). MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases. International Journal of Oncology, 63, 140. https://doi.org/10.3892/ijo.2023.5588
MLA
Zheng, Z., Chen, X., Zhang, Y., Ren, F., Ma, Y."MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases". International Journal of Oncology 63.6 (2023): 140.
Chicago
Zheng, Z., Chen, X., Zhang, Y., Ren, F., Ma, Y."MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases". International Journal of Oncology 63, no. 6 (2023): 140. https://doi.org/10.3892/ijo.2023.5588
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Spandidos Publications style
Zheng Z, Chen X, Zhang Y, Ren F and Ma Y: MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases. Int J Oncol 63: 140, 2023.
APA
Zheng, Z., Chen, X., Zhang, Y., Ren, F., & Ma, Y. (2023). MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases. International Journal of Oncology, 63, 140. https://doi.org/10.3892/ijo.2023.5588
MLA
Zheng, Z., Chen, X., Zhang, Y., Ren, F., Ma, Y."MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases". International Journal of Oncology 63.6 (2023): 140.
Chicago
Zheng, Z., Chen, X., Zhang, Y., Ren, F., Ma, Y."MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases". International Journal of Oncology 63, no. 6 (2023): 140. https://doi.org/10.3892/ijo.2023.5588
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