PRMT1-RBM15 axis regulates megakaryocytic differentiation of human umbilical cord blood CD34+ cells

Jin,Shuiling; Mi,Yanfang; Song,Jing; Zhang,Peipei; Liu,Yanyan

doi:10.3892/etm.2018.5693

PRMT1-RBM15 axis regulates megakaryocytic differentiation of human umbilical cord blood CD34+ cells

Authors:
- Shuiling Jin
- Yanfang Mi
- Jing Song
- Peipei Zhang
- Yanyan Liu
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Affiliations: Department of Internal Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China, Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China, Department of Internal Medicine, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
Published online on: January 4, 2018 https://doi.org/10.3892/etm.2018.5693
Pages: 2563-2568

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Abstract

Protein arginine methyltransferase 1 (PRMT1) serves pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has not been clearly reported. The aim of the present study was to explore the role of the PRMT‑RNA binding motif protein 15 (RBM15) axis in human MK differentiation and the feasibility of targeting PRMT1 for leukemia treatment. In the present study, PRMT1 was overexpressed and the RBM15 protein was knocked down in human umbilical cord blood cluster of differentiation (CD)34+ cells and the cells were then cultured in megakaryocytic differentiation medium. Flow cytometry was used to analyze CD41 and CD42 double‑positive cells, as well as the protein expression levels of PRMT1 and RBM15. The results demonstrated that human cord blood CD34+ cells differentiate into mature MKs in high thrombopoitin medium, as demonstrated by CD41 and CD42 expression. Overexpression of PRMT1 in human umbilical cord blood CD34+ cells blocked the maturation of megakaryocytic cells. Knockdown of RBM15 by short hairpin RNA produced less mature MKs. PRMT1 inhibitor rescued PRMT1‑blocked megakaryocytic differentiation. These results provide evidence for a novel role of PRMT1 in the negative regulation of megakaryocytic differentiation. PRMT1 may be a therapeutic target for leukemia treatment.

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1	Bourquin JP, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P, Baruchel A, Cavé H, Dastugue N, Hasle H, et al: Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA. 103:pp. 3339–3344. 2006; View Article : Google Scholar : PubMed/NCBI
2	Je EM, Yoo NJ, Kim YJ, Kim MS and Lee SH: Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors. Int J Cancer. 133:260–265. 2013. View Article : Google Scholar : PubMed/NCBI
3	Yamamoto S, Toyama D, Yatsuki H, Higashimoto K, Soejima H and Isoyama K: Acute megakaryocytic leukemia (AMKL, FAB;M7) with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer. 55:733–735. 2010. View Article : Google Scholar : PubMed/NCBI
4	Han Y, Tang Y, Chen J, Liang J, Ye C, Ruan C and Wu D: Low-dose decitabine for patients with thrombocytopenia following allogeneic hematopoietic stem cell transplantation: A pilot therapeutic study. JAMA Oncol. 1:249–251. 2015. View Article : Google Scholar : PubMed/NCBI
5	Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, et al: Oncomine 3.0: Genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 9:166–180. 2007. View Article : Google Scholar : PubMed/NCBI
6	Zolotukhin AS, Uranishi H, Lindtner S, Bear J, Pavlakis GN and Felber BK: Nuclear export factor RBM15 facilitates the access of DBP5 to mRNA. Nucleic Acids Res. 37:7151–7162. 2009. View Article : Google Scholar : PubMed/NCBI
7	Xiao N, Laha S, Das SP, Morlock K, Jesneck JL and Raffel GD: Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl. Blood. 125:941–948. 2015. View Article : Google Scholar : PubMed/NCBI
8	Zhang L, Tran NT, Su H, Wang R, Lu Y, Tang H, Aoyagi S, Guo A, Khodadadi-Jamayran A, Zhou D, et al: Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. eLife. 4:pii: e079382015. View Article : Google Scholar
9	Chang HC, Jones OW, Bradshaw C, Sarkar S and Porreco RP: Enhancement of human amniotic cell growth by Ficoll-Paque gradient fractionation. In Vitro. 17:81–90. 1981. View Article : Google Scholar : PubMed/NCBI
10	Yang Z, Augustin J, Chang C, Hu J, Shah K, Chang CW, Townes T and Jiang H: The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells. Blood. 124:2025–2033. 2014. View Article : Google Scholar : PubMed/NCBI
11	Horiuchi K, Kawamura T, Iwanari H, Ohashi R, Naito M, Kodama T and Hamakubo T: Identification of Wilms' tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J Biol Chem. 288:33292–33302. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lee JH and Skalnik DG: Rbm15-Mkl1 interacts with the Setd1b histone H3-Lys4 methyltransferase via a SPOC domain that is required for cytokine-independent proliferation. PLoS One. 7:e429652012. View Article : Google Scholar : PubMed/NCBI
13	Vu LP, Perna F, Wang L, Voza F, Figueroa ME, Tempst P, Erdjument-Bromage H, Gao R, Chen S, Paietta E, et al: PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep. 5:1625–1638. 2013. View Article : Google Scholar : PubMed/NCBI
14	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. View Article : Google Scholar : PubMed/NCBI
15	Gao Y, Smith E, Ker E, Campbell P, Cheng EC, Zou S, Lin S, Wang L, Halene S and Krause DS: Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes. Dev Cell. 22:573–584. 2012. View Article : Google Scholar : PubMed/NCBI
16	Bedford MT and Clarke SG: Protein arginine methylation in mammals: Who, what, and why. Mol Cell. 33:1–13. 2009. View Article : Google Scholar : PubMed/NCBI
17	Mathioudaki K, Papadokostopoulou A, Scorilas A, Xynopoulos D, Agnanti N and Talieri M: The PRMT1 gene expression pattern in colon cancer. Br J Cancer. 99:2094–2099. 2008. View Article : Google Scholar : PubMed/NCBI
18	Chang YI, Hua WK, Yao CL, Hwang SM, Hung YC, Kuan CJ, Leou JS and Lin WJ: Protein-arginine methyltransferase 1 suppresses megakaryocytic differentiation via modulation of the p38 MAPK pathway in K562 cells. J Biol Chem. 285:20595–20606. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X, Bouman D, Li Y, Mehta PK, Nizetic D, et al: Fusion of two novel genes, RBM15 and MKL1, in the t(1;22) (p13; q13) of acute megakaryoblastic leukemia. Nat Genet. 28:220–221. 2001. View Article : Google Scholar : PubMed/NCBI
20	Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac F, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R and Bernard OA: Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci USA. 98:pp. 5776–5779. 2001; View Article : Google Scholar : PubMed/NCBI
21	Baldwin RM, Morettin A, Paris G, Goulet I and Côté J: Alternatively spliced protein arginine methyltransferase 1 isoform PRMT1v2 promotes the survival and invasiveness of breast cancer cells. Cell Cycle. 11:4597–4612. 2012. View Article : Google Scholar : PubMed/NCBI
22	Mercher T, Raffel GD, Moore SA, Cornejo MG, Baudry-Bluteau D, Cagnard N, Jesneck JL, Pikman Y, Cullen D, Williams IR, et al: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest. 119:852–864. 2009.PubMed/NCBI
23	Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, Tomotaka S, Morton LM, Weisenburger DD and Matsuo K: Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol. 164:536–545. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yan L, Yan C, Qian K, Su H, Kofsky-Wofford SA, Lee WC, Zhao X, Ho MC, Ivanov I and Zheng YG: Diamidine compounds for selective inhibition of protein arginine methyltransferase 1. J Med Chem. 57:2611–2622. 2014. View Article : Google Scholar : PubMed/NCBI