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Expressional changes of genes and miRNA in common megakaryocyte-erythroid progenitors from lower-risk myelodysplastic syndrome

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Abstract

Myelodysplastic syndrome (MDS) is a stem cell tumor characterized by dysplastic features and ineffective hematopoiesis in the early phase and leukemic progression in the late phase. Speculating that differences in the expression of genes and microRNA (miRNA) in control and MDS-derived erythroid progenitors may cause ineffective erythropoiesis, we sorted common megakaryocyte-erythroid progenitors (MEPs) in bone marrow cells from three lower-risk MDS patients, and compared expression levels of genes and miRNA with those from controls. In apoptosis-related pathways, the expression of some pro-apoptotic genes, such as cell death-inducing DFFA-like effector A, caspase 5, and Fas ligand, was elevated in MDS-derived MEPs, while those of anti-apoptotic CD40 and tumor necrosis factor were lower. In hematopoiesis-regulating pathways, RUNX1 and ETV6 genes showed reduced expression. Expression profiling revealed that three and 35 miRNAs were significantly up- and down-regulated in MDS-derived MEPs. MIR9 exhibited robust expression in MEPs and CD71+GlyA+ erythroid cells derived from one of the three patients. Interestingly, overexpression of MIR9 inhibited the accumulation of hemoglobin in UT-7/GM cells. Some of these alterations in gene and miRNA expression may contribute to the pathogenesis of ineffective hematopoiesis in lower-risk MDS and provide molecular markers for sub-classification and making a prognosis.

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References

  1. Yamazaki H, Nakao S. Border between aplastic anemia and myelodysplastic syndrome. Int J Hematol. 2013;97:558–63.

    Article  PubMed  CAS  Google Scholar 

  2. Yamazaki J, Issa JP. Epigenetic aspects of MDS and its molecular targeted therapy. Int J Hematol. 2013;97:175–82.

    Article  PubMed  CAS  Google Scholar 

  3. Daver N, Strati P, Jabbour E, Kadia T, Luthra R, Wang S, et al. FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. Am J Hematol. 2013;88:56–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Hirai H, Kobayashi Y, Mano H, Hagiwara K, Maru Y, Omine M, et al. A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. Nature. 1987;327:430–2.

    Article  PubMed  CAS  Google Scholar 

  5. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M. A role for RUNX1 in hematopoiesis and myeloid leukemia. Int J Hematol. 2013;97:726–34.

    Article  PubMed  CAS  Google Scholar 

  6. Bohlander SK. ETV6: a versatile player in leukemogenesis. Semin Cancer Biol. 2005;15:162–74.

    Article  PubMed  CAS  Google Scholar 

  7. Adamson DJ, Dawson AA, Bennett B, King DJ, Haites NE. p53 mutation in the myelodysplastic syndromes. Br J Haematol. 1995;89:61–6.

    Article  PubMed  CAS  Google Scholar 

  8. Walter MJ, Ding L, Shen D, Shao J, Grillot M, McLellan M, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25:1153–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.

    Article  PubMed  Google Scholar 

  10. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–42.

    Article  PubMed  CAS  Google Scholar 

  11. Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia. 2010;24:1094–6.

    Article  PubMed  CAS  Google Scholar 

  12. Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145:788–800.

    Article  PubMed  CAS  Google Scholar 

  13. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.

    Article  PubMed  CAS  Google Scholar 

  14. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.

    Article  PubMed  CAS  Google Scholar 

  15. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.

    Article  PubMed  CAS  Google Scholar 

  16. Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, Szpurka H, et al. 250 K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008;68:10349–57.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904–8.

    Article  PubMed  CAS  Google Scholar 

  18. Sanada M, Ogawa S. Genome-wide analysis of myelodysplastic syndromes. Curr Pharm Des. 2012;18:3163–9.

    Article  PubMed  CAS  Google Scholar 

  19. Bhagat TD, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K, et al. miR-21 mediates hematopoietic suppression in MDS by activating TGF-beta signaling. Blood. 2013;121:2875–81.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Lu J, Guo S, Ebert BL, Zhang H, Peng X, Bosco J, et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell. 2008;14:843–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Maki K, Yamagata T, Sugita F, Nakamura Y, Sasaki K, Mitani K. Aberrant expression of MIR9 indicates poor prognosis in acute myeloid leukaemia. Br J Haematol. 2012;158:283–5.

    Article  PubMed  CAS  Google Scholar 

  23. Miyazato A, Ueno S, Ohmine K, Ueda M, Yoshida K, Yamashita Y, et al. Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction. Blood. 2001;98:422–7.

    Article  PubMed  CAS  Google Scholar 

  24. Hofmann WK, de Vos S, Komor M, Hoelzer D, Wachsman W, Koeffler HP. Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow. Blood. 2002;100:3553–60.

    Article  PubMed  CAS  Google Scholar 

  25. Chen G, Zeng W, Miyazato A, Billings E, Maciejewski JP, Kajigaya S, et al. Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood. 2004;104:4210–8.

    Article  PubMed  CAS  Google Scholar 

  26. Abe S, Yamamoto K, Hasegawa M, Inoue M, Kurata M, Hirokawa K, et al. Bone marrow cells of myelodysplastic syndromes exhibit significant expression of apollon, livin and ILP-2 with reduction after transformation to overt leukemia. Leuk Res. 2005;29:1095–6.

    Article  PubMed  CAS  Google Scholar 

  27. Dallman C, Johnson PW, Packham G. Differential regulation of cell survival by CD40. Apoptosis. 2003;8:45–53.

    Article  PubMed  CAS  Google Scholar 

  28. So T, Lee SW, Croft M. Tumor necrosis factor/tumor necrosis factor receptor family members that positively regulate immunity. Int J Hematol. 2006;83:1–11.

    Article  PubMed  CAS  Google Scholar 

  29. Luger SM, Ratajczak J, Ratajczak MZ, Kuczynski WI, DiPaola RS, Ngo W, et al. A functional analysis of protooncogene Vav’s role in adult human hematopoiesis. Blood. 1996;87:1326–34.

    PubMed  CAS  Google Scholar 

  30. Kurokawa M. AML1/Runx1 as a versatile regulator of hematopoiesis: regulation of its function and a role in adult hematopoiesis. Int J Hematol. 2006;84:136–42.

    Article  PubMed  CAS  Google Scholar 

  31. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood. 2000;96:3154–60.

    PubMed  CAS  Google Scholar 

  32. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood. 2003;101:673–80.

    Article  PubMed  CAS  Google Scholar 

  33. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood. 2004;103:2316–24.

    Article  PubMed  CAS  Google Scholar 

  34. Demers C, Chaturvedi CP, Ranish JA, Juban G, Lai P, Morle F, et al. Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus. Mol Cell. 2007;27:573–84.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Hussein K, Theophile K, Busche G, Schlegelberger B, Gohring G, Kreipe H, et al. Aberrant microRNA expression pattern in myelodysplastic bone marrow cells. Leuk Res. 2010;34:1169–74.

    Article  PubMed  CAS  Google Scholar 

  36. Dostalova Merkerova M, Krejcik Z, Votavova H, Belickova M, Vasikova A, Cermak J. Distinctive microRNA expression profiles in CD34 + bone marrow cells from patients with myelodysplastic syndrome. Eur J Hum Genet. 2011;19:313–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Erdogan B, Facey C, Qualtieri J, Tedesco J, Rinker E, Isett RB, et al. Diagnostic microRNAs in myelodysplastic syndrome. Exp Hematol. 2011;39(915–26):e2.

    PubMed  Google Scholar 

  38. Sokol L, Caceres G, Volinia S, Alder H, Nuovo GJ, Liu CG, et al. Identification of a risk dependent microRNA expression signature in myelodysplastic syndromes. Br J Haematol. 2011;153:24–32.

    Article  PubMed  CAS  Google Scholar 

  39. Votavova H, Grmanova M, Dostalova Merkerova M, Belickova M, Vasikova A, Neuwirtova R, et al. Differential expression of microRNAs in CD34+ cells of 5q- syndrome. J Hematol Oncol. 2011;4:1.

  40. Pons A, Nomdedeu B, Navarro A, Gaya A, Gel B, Diaz T, et al. Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma. 2009;50:1854–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Ms. A. Okada for her special technical assistance. This work was financially supported by Grants-in-Aid from the Ministries of Education, Culture, Sports, Science and Technology (17016068), and Health, Labour and Welfare, Japan, the Japanese Society for the Promotion of Science (20390275, 18591086, 50337391), and Seki Minato Award from Dokkyo Medical University School of Medicine.

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The authors declare that they have no conflict of interest.

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Correspondence to Kinuko Mitani.

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Maki, K., Sasaki, K., Nagata, Y. et al. Expressional changes of genes and miRNA in common megakaryocyte-erythroid progenitors from lower-risk myelodysplastic syndrome. Int J Hematol 100, 361–369 (2014). https://doi.org/10.1007/s12185-014-1639-2

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  • DOI: https://doi.org/10.1007/s12185-014-1639-2

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