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The role of phosphorylation of MLF2 at serine 24 in BCR-ABL leukemogenesis

Cancer Gene Therapy volume 27, pages 98–107 (2020)Cite this article

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Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder defined by the presence of the fusion gene BCR-ABL1 in primitive hematopoietic progenitors. The myeloid leukemia factors (MLFs) were identified in the fly and human, and are involved in acute leukemia and enhancing the myeloid factor; however, the function of MLF2 in CML is poorly understood. In this study, we demonstrated that MLF2 may play an oncogenic role in CML. The expression level of MLF2 was related to the proliferation, colony-formation ability, and sensitivity to imatinib in K562 cells. Moreover, phosphorylation at serine 24, detected through Phos-tag sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was required to maintain the activity of MLF2 in CML. The effects of MLF2 overexpression on the colony-formation ability in vitro and mouse survival in vivo could be alleviated by point mutation of MLF2 at serine 24. These findings uncover the oncogenic role of MLF2 through phosphorylation at serine 24 and provide a novel therapeutic target in CML.

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Fig. 1: Effects of MLF2 on the malignant progression of CML.
Fig. 2: Effects of targeting MLF2 in K562 cells.
Fig. 3: Phosphorylation at S24 is sufficient to maintain the activity of MLF2.
Fig. 4: Effects of MLF2 phosphorylation at S24 on a CML xenograft murine model.
Fig. 5: Signaling pathways downstream of MLF2.

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References

  1. Chu S, Li L, Singh H, Bhatia R. BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer Res. 2007;67:7045–53.

    Article  CAS  Google Scholar 

  2. Sawyers CL. Chronic myeloid leukemia. New Engl J Med. 1999;340:1330–40.

    Article  CAS  Google Scholar 

  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New Engl J Med. 2001;344:1031–7.

    Article  CAS  Google Scholar 

  4. Corbin AS, O'Hare T, Gu Z, Kraft IL, Eiring AM, Khorashad JS, et al. KIT signaling governs differential sensitivity of mature and primitive CML progenitors to tyrosine kinase inhibitors. Cancer Res. 2013;73:5775–86.

    Article  CAS  Google Scholar 

  5. Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 2017;130:410–23.

    Article  CAS  Google Scholar 

  6. Bras S, Martin-Lanneree S, Gobert V, Auge B, Breig O, Sanial M, et al. Myeloid leukemia factor is a conserved regulator of RUNX transcription factor activity involved in hematopoiesis. Proc Natl Acad Sci USA. 2012;109:4986–91.

    Article  CAS  Google Scholar 

  7. Winteringham LN, Kobelke S, Williams JH, Ingley E, Klinken SP. Myeloid leukemia factor 1 inhibits erythropoietin-induced differentiation, cell cycle exit and p27Kip1 accumulation. Oncogene. 2004;23:5105–9.

    Article  CAS  Google Scholar 

  8. Kuefer MU, Look AT, Williams DC, Valentine V, Naeve CW, Behm FG, et al. cDNA cloning, tissue distribution, and chromosomal localization of myelodysplasia/myeloid leukemia factor 2 (MLF2). Genomics. 1996;35:392–6.

    Article  CAS  Google Scholar 

  9. Choudhury KR, Raychaudhuri S, Bhattacharyya NP. Identification of HYPK-interacting proteins reveals involvement of HYPK in regulating cell growth, cell cycle, unfolded protein response and cell death. PLoS ONE. 2012;7:e51415.

    Article  Google Scholar 

  10. Banerjee M, Datta M, Bhattacharyya NP. Modulation of mutant Huntingtin aggregates and toxicity by human myeloid leukemia factors. Int J Biochem Cell Biol. 2017;82:1–9.

    Article  CAS  Google Scholar 

  11. Dave B, Granados-Principal S, Zhu R, Benz S, Rabizadeh S, Soon-Shiong P, et al. Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci USA. 2014;111:8838–43.

    Article  CAS  Google Scholar 

  12. Hunter T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 1995;80:225–36.

    Article  CAS  Google Scholar 

  13. Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, et al. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993;75:175–85.

    Article  CAS  Google Scholar 

  14. Gerboth S, Frittoli E, Palamidessi A, Baltanas FC, Salek M, Rappsilber J, et al. Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis. Leukemia. 2018;32:820–7.

    Article  CAS  Google Scholar 

  15. Kinoshita E, Kinoshita-Kikuta E, Takiyama K, Koike T. Phosphate-binding tag, a new tool to visualize phosphorylated proteins. Mol Cell Proteomics. 2006;5:749–57.

    Article  CAS  Google Scholar 

  16. de Bruijn M, Dzierzak E. Runx transcription factors in the development and function of the definitive hematopoietic system. Blood. 2017;129:2061–9.

    Article  Google Scholar 

  17. Yu J, Deshmukh H, Payton JE, Dunham C, Scheithauer BW, Tihan T, et al. Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. Clin Cancer Res. 2011;17:1924–34.

    Article  CAS  Google Scholar 

  18. Miller M, Chen A, Gobert V, Auge B, Beau M, Burlet-Schiltz O, et al. Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis. PLoS Genet. 2017;13:e1006932.

    Article  Google Scholar 

  19. Lala PK, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol. 2001;2:149–56.

    Article  CAS  Google Scholar 

  20. Chowdhury AA, Chaudhuri J, Biswas N, Manna A, Chatterjee S, Mahato SK, et al. Synergistic apoptosis of CML cells by buthionine sulfoximine and hydroxychavicol correlates with activation of AIF and GSH-ROS-JNK-ERK-iNOS pathway. PloS ONE. 2013;8:e73672.

    Article  CAS  Google Scholar 

  21. Gallipoli P, Cook A, Rhodes S, Hopcroft L, Wheadon H, Whetton AD, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124:1492–501.

    Article  CAS  Google Scholar 

  22. Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72:2337–47.

    Article  CAS  Google Scholar 

  23. Juan WC, Ong ST. The role of protein phosphorylation in therapy resistance and disease progression in chronic myelogenous leukemia. Prog Mol Biol Transl Sci. 2012;106:107–42.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81170496), Research Project for Practice Development of National TCM Clinical Research Bases (No. JDZX2015119), Science and Technology Program of Guangdong Province (Nos. 2014A020212729, 2016A020226027), Science and Technology Program of Guangzhou City (No. 201504281729050), and the Fundamental Research Funds for the Central Universities (No. 21617461).

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Author notes

  1. These authors contributed equally: Juhua Yang, Donglin Cao, Yanrong Zhang

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou, 510632, China

    Juhua Yang, Zhao Yin, Yanjun Liu, Guiping Huang, Chunming Gu & Jia Fei

  2. Engineering Technology Research Center of Drug Development for Small Nucleic Acid of Guangdong Province, Guangzhou, 510632, China

    Juhua Yang, Zhao Yin, Yanjun Liu, Guiping Huang, Chunming Gu & Jia Fei

  3. Antisense Biopharmaceutical Technology Co., Ltd, Guangzhou, 510632, China

    Juhua Yang, Zhao Yin, Yanjun Liu, Guiping Huang, Chunming Gu & Jia Fei

  4. Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China

    Donglin Cao

  5. Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, 510317, China

    Yanrong Zhang & Shengting Chen

  6. Department of Hematology, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China

    Ruiming Ou

  7. Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou, 510632, China

    Zhao Yin, Chunming Gu & Jia Fei

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  1. Juhua Yang
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Contributions

JF conceived and designed the experiments. JY, YZ, and GH performed the experiments. JY, YL, DC, and GH analyzed the data. OR, ZY, CG, and YL contributed reagents, materials, and analytical tools. DC, OR, and CS prepared the normal and patients sample. JF, JY, and ZY wrote the paper.

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Correspondence to Jia Fei.

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Yang, J., Cao, D., Zhang, Y. et al. The role of phosphorylation of MLF2 at serine 24 in BCR-ABL leukemogenesis. Cancer Gene Ther 27, 98–107 (2020). https://doi.org/10.1038/s41417-019-0152-4

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