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Immunogenetics

, Volume 63, Issue 6, pp 337–350 | Cite as

YBX1 expression and function in early hematopoiesis and leukemic cells

  • Jasjeet Bhullar
  • Vincent E. Sollars
Original Paper

Abstract

Hematopoietic transcription factors play a critical role in directing the commitment and differentiation of hematopoietic stem cells along a particular lineage. Y-box protein (YBX1) is a transcription factor which is widely expressed throughout development and is involved in erythroid cell development; however, its role in early hematopoietic differentiation is not known. This study aims to investigate the role of YBX1 expression in early hematopoietic differentiation and leukemia. Here, we show that YBX1 is highly expressed in mouse erythroid myeloid lymphoid-clone 1 (EML), a hematopoietic precursor cell line, but is down-regulated in myeloid progenitors and GM-CSF-treated EML cells during the course of myeloid differentiation. Moreover, we found that lineage/IL-7R/c-kit+/Sca1+ (LKS; enriched fraction of hematopoietic stem cells) and lineage/IL-7R/c-kit+/Sca1 myeloid progenitor cells showed high level of YBX1 expression as compared to the differentiated cells like granulocytes in mouse bone marrow. Also, YBX1 protein was expressed at high levels in myeloid leukemic cell lines blocked at different stages of myeloid development. We further investigated the role of YBX1 in leukemic cells by knockdown studies and observed that down-regulation of YBX1 expression in K562 leukemic cells inhibited their proliferation ability, induced apoptosis, and differentiation towards megakaryocytic lineage upon arsenic trioxide treatments relative to untreated. Overall, our data indicates that YBX1 is down-regulated during myeloid differentiation and the aberrant YBX1 expression in leukemic cells could be a contributing factor in the development of leukemia by blocking their differentiation. Thus, YBX1 protein could be an excellent molecular target for therapy in myeloproliferative disorders and leukemia.

Keywords

YBX1 EML cells K562 cells Differentiation Mouse stem and progenitor cells 

Notes

Acknowledgements

We thank Dr. Schickwann Tsai for the generous gift of EML cell line used in this study. We also thank Dr. Thomas Iftner and Dr Johanna Schuetz for donating pSUPER YBX1 shRNA and pSUPER EV (Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tuebingen, Tuebingen, Germany). We gratefully acknowledge the advice and constructive discussion of Dr. Sandeep Joshi. This work was supported in part by NIH NCRR COBRE (5P20RR020180) and WV-INBRE (5P20RR016477) grants which support the Marshall University Genomics Core Facility and the Marshall University Flow Cytometry Core Facility. This work was also supported by the NIH/NCI by R03CA129790.

Conflict of interest disclosure

The authors declare no competing financial interests.

References

  1. Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404:193–197PubMedCrossRefGoogle Scholar
  2. Baliga BS, Mankad M, Shah AK, Mankad VN (1993) Mechanism of differentiation of human erythroleukaemic cell line K562 by Hemin. Cell Prolif 26:519–529PubMedCrossRefGoogle Scholar
  3. Chatterjee M, Rancso C, Stühmer T et al (2008) The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma. Blood 111:3714–3722PubMedCrossRefGoogle Scholar
  4. Coles LS, Diamond P, Occhiodoro F, Vadas MA, Shannon MF (1996) Cold shock domain proteins repress transcription from the GM-CSF promoter. Nucleic Acids Res 24:2311–2317PubMedCrossRefGoogle Scholar
  5. Collins SJ (2002) The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16:1896–1905PubMedCrossRefGoogle Scholar
  6. de Souza-Pinto NC, Mason PA, Hashiguchi K et al (2009) Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst) 8(6):704–719CrossRefGoogle Scholar
  7. Evdokimova V, Ovchinnikov L, Sorensen P (2006) Y-box binding protein 1: providing a new angle on translational regulation. Cell Cycle 5:1143–1147PubMedCrossRefGoogle Scholar
  8. Fukuda T, Ashizuka M, Nakamura T et al (2004) Characterization of the 5′-untranslated region of YB-1 mRNA and autoregulation of translation by YB-1 protein. Nucleic Acids Res 32:611–622PubMedCrossRefGoogle Scholar
  9. Greenberg P, Cox C, Le Beau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMedGoogle Scholar
  10. Huber E, Vlasny D, Jeckel S, Stubenrauch F, Iftner T (2004) Gene profiling of cottontail rabbit papillomavirus-induced carcinomas identifies upregulated genes directly involved in stroma invasion as shown by small interfering RNA-mediated gene silencing. J Virol 78:7478PubMedCrossRefGoogle Scholar
  11. Huntley BJ, Gilliland DG (2005) Leukemia stem cells and the evolution of cancer-stem cell research. Nat Rev Cancer 5:311–321CrossRefGoogle Scholar
  12. Jamieson CH, Ailles LE, Dylla SJ et al (2004) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast crisis CML. N Engl J Med 351:657–667PubMedCrossRefGoogle Scholar
  13. Johnson BS, Chandraratna RA, Heyman RA, Allegretto EA, Mueller L, Collins SJ (1999) Retinoid X receptor (RXR) agonist-induced activation of dominant-negative RXR-retinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation. Mol Cell Biol 19(5):3372–3382PubMedGoogle Scholar
  14. Jurchott K, Bergmann S, Stein U (2003) YB-1 as a cell cycle-regulated transcription factor facilitating cyclin A and cyclin B1 gene expression. J Biol Chem 278:27988–27996PubMedCrossRefGoogle Scholar
  15. Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M (2003) The pleiotropic functions of the Y-box binding protein, YB-1. Bioessays 25:691–698PubMedCrossRefGoogle Scholar
  16. Kuwano M, Oda Y, Izumi H et al (2004) The role of nuclear Y-box binding protein 1 as a global marker in drug resistance. Mol Cancer Ther 3:1485–1492PubMedGoogle Scholar
  17. Ladomery M, Sommerville J (1995) A role for Y-box proteins in cell proliferation. Bioessays 17:9–11PubMedCrossRefGoogle Scholar
  18. Lasham A, Lindridge E, Rudert F, Onrust R, Watson J (2000) Regulation of the human fas promoter by YB-1, Puralpha and AP-1 transcription factors. Gene 252:1–13PubMedCrossRefGoogle Scholar
  19. Lee YT, Miller LD, Gubin AN, Makhlouf F, Wojda U, Barrett AJ (2001) Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays. Blood 98:1914–1921PubMedCrossRefGoogle Scholar
  20. Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45(3):321–334PubMedGoogle Scholar
  21. Lu ZH, Books JT, Ley TJ (2005) YB-1 is important for late-stage embryonic development, optimal cellular stress responses, and the prevention of premature senescence. Mol Cell Biol 25:4625–4637PubMedCrossRefGoogle Scholar
  22. Ma X, Husain T, Peng H et al (2002) Development of a murine hematopoietic progenitor complementary DNA microarray using a subtracted complementary DNA library. Blood 100:833–844PubMedCrossRefGoogle Scholar
  23. Mertens PR, Harendza S, Pollock AS, Lovett DH (1997) Glomerular mesangial cell-specific transactivation of matrix metalloproteinase 2 transcription is mediated by YB-1. J Biol Chem 272(22905):12Google Scholar
  24. Ohga T, Uchiumi T, Makino Y et al (1998) Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance1 gene. J Biol Chem 273:5997–6000PubMedCrossRefGoogle Scholar
  25. Rosenbauer F, Koschmieder S, Steidl U, Tenen DG (2005) Effect of transcription-factor concentrations on leukemic stem cells. Blood 106:1519–1524PubMedCrossRefGoogle Scholar
  26. Schittek B, Psenner K, Sauer B, Meier F, Iftner T, Garbe C (2007) The increased expression of Y box-binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistance. Int J Cancer 120:2110–2118PubMedCrossRefGoogle Scholar
  27. Shibahara K, Uchiumi T, Fukuda T et al (2004) Targeted disruption of one allele of the Y-box binding protein-1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C. Cancer Sci 95:348–353PubMedCrossRefGoogle Scholar
  28. Szalai G, LaRue AC, Watson DK (2006) Molecular mechanisms of megakaryopoiesis. Cell Mol Life Sci 63(21):2460–2476PubMedCrossRefGoogle Scholar
  29. Tabilio A, Pelicei PG (1983) Myeloid and megakaryocytic properties of K-562 cell lines. Cancer Res 43:4569–4574PubMedGoogle Scholar
  30. Tang W, Chen G, Shi G (1997) Double effects of arsenic trioxide (As2O3) on acute promyelocytic leukemic cell line. Zhonghua Yi Xue Za Zhi 77(7):509–512PubMedGoogle Scholar
  31. Tenen DG, Hromas R, Licht JD, Zhang DE (1997) Transcription factors, normal myeloid development, and leukemia. Blood 90:489–519PubMedGoogle Scholar
  32. Tichopad A, Dilger M, Schwarz G, Pfaffl MW (2003) Standardized determination of real-time PCR efficiency from a single reaction set-up. Nucleic Acids Res 31:e122PubMedCrossRefGoogle Scholar
  33. Toh S, Nakamura T, Ohga T et al (1998) Genomic organization of the human Y-box protein (YB-1) gene. Gene 206:93–97PubMedCrossRefGoogle Scholar
  34. Tsai S, Bartelmez S, Sitnicka E, Collins S (1994) Lymphohematopoietic progenitors immortalized by a retroviral vector harboring a dominant-negative retinoic acid receptor can recapitulate lymphoid, myeloid, and erythroid development. Genes Dev 8:2831–2841PubMedCrossRefGoogle Scholar
  35. Vitrat N, Cohen-Solal K, Pique C (1998) Endomitosis of human megakaryocytes are due to abortive mitosis. Blood 91(10):3711–3723PubMedGoogle Scholar
  36. Wolfe AP (1994) Structural and functional properties of the evolutionarily ancient Y-box family of nucleic acid binding proteins. Bioessays 16:245–251CrossRefGoogle Scholar
  37. Wu J, Stratford AL, Astanehe A, Dunn SE (2007) YB-1 is a transcription/translation factor that orchestrates the oncogenome by hardwiring signal transduction to gene expression. Translational Oncogenomics 2:49–65Google Scholar
  38. Xu WL, Zhou LL, Chen QY, Chen C, Fang LL, Fang XJ, Shen HL (2009) Effect of YB-1 gene knockdown on human leukemia cell line K562/A02. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(4):400–405Google Scholar
  39. Ye ZJ, Kluger Y, Lian Z, Weissman SM (2005) Two types of precursor cells in a multipotential hematopoietic cell line. Proc Natl Acad Sci USA 102(51):18461–18466PubMedCrossRefGoogle Scholar
  40. Yokoyama H, Harigae H, Takahashi S et al (2003a) High expression of YB-1 gene in erythroid cells in patients with refractory anemia. Int J Hematol 78:213–218CrossRefGoogle Scholar
  41. Yokoyama H, Harigae H, Takahashi S et al (2003b) Regulation of YB-1 gene expression by GATA transcription factors. Biochem Biophys Res Commun 303:140–145CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Biochemistry and Microbiology, Joan C. Edwards School of MedicineMarshall UniversityHuntingtonUSA
  2. 2.Department of Biochemistry and Microbiology, One John Marshall Drive (BBSC)Marshall UniversityHuntingtonUSA

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