MicroRNA-125b-1 accelerates a C-terminal mutant of C/EBPα (C/EBPα-Cm)-induced myeloid leukemia (original) (raw)

Abstract

_MicroRNA_-_125b_-1 (_miR_-_125b_-1) is a target of the chromosomal translocations t(11;14)(q24;q32) and t(2;11)(p21;q23), which are found in human B-lymphoid and myeloid malignancies, respectively. These translocations result in overexpression of mature miR-125b, consisting of 22 nucleotides. To analyze the role of _miR_-_125b_-1 in leukemogenesis, we created a bone marrow transplantation model using a retrovirus vector containing GFP expression elements. Sole transduction of _miR_-_125b_-1 into bone marrow cells resulted in expansion of hematopoietic cells expressing GFP. Compared with cells lacking GFP expression, we observed that GFP+/CD11b+ or GFP+/Gr−1+ cells were increased in the bone marrow and spleen. Although previous studies reported sole induction of miR-125b-induced leukemia, we did not find leukemic transformation in our model. Transduction of _miR_-_125b_-1 did accelerate myeloid tumors induced by a C-terminal mutant of CAAT-enhancer binding protein (C/EBPα-Cm), a class II-like mutation. As miR-125b has been shown to hasten the development of leukemia in a BCR/ABL-transduced animal model, our present results support the conclusion that overexpression of miR-125b cooperates with other genetic alterations in the pathogenesis of myeloid malignancies.

Access this article

Log in via an institution

Subscribe and save

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sonoki T, Iwanaga E, Mitsuya H, Asou N. Insertion of microRNA-125b-1, a human homologue of lin-4, into a rearranged immunoglobulin heavy chain gene locus in a patient with precursor B-cell acute lymphoblastic leukemia. Leukemia. 2005;19:2009–10.
    Article PubMed CAS Google Scholar
  2. Chapiro E, Russell LJ, Struski S, Cavé H, Radford-Weiss I, Valle VD, et al. A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia. 2010;24(7):1362–4.
    Article PubMed CAS Google Scholar
  3. Tassano E, Acquila M, Tavella E, Micalizzi C, Panarello C, Morerio C. MicroRNA-125b-1 and BLID upregulation resulting from a novel IGH translocation in childhood B-Cell precursor acute lymphoblastic leukemia. Genes Chromosom Cancer. 2010;49:682–7.
    Article PubMed CAS Google Scholar
  4. Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J, Akasaka T, Kato N, et al. Eμ/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia. 2011;25:1849–56.
    Article PubMed CAS Google Scholar
  5. Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C, et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J Exp Med. 2008;205:2499–506.
    Article PubMed CAS Google Scholar
  6. O’Connell RM, Chaudhuri AA, Rao DS, Gibson WS, Balazs AB, Baltimore D. MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc Natl Acad Sci USA. 2010;107:14235–40.
    Article PubMed Google Scholar
  7. Ooi AG, Sahoo D, Adorno M, Wang Y, Weissman IL, Park CY. MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets. Proc Natl Acad Sci USA. 2010;107:21505–10.
    Article PubMed CAS Google Scholar
  8. Bousquet M, Harris MH, Zhou B, Lodish HF. MicroRNA miR-125b causes leukemia. Proc Natl Acad Sci USA. 2010;107:21558–63.
    Article PubMed CAS Google Scholar
  9. Somervaille TC, Cleary ML. Grist for the MLL: how do MLL oncogenic fusion proteins generate leukemia stem cells? Int J Hematol. 2010;91:735–41.
    Article PubMed Google Scholar
  10. Goyama S, Mulloy JC. Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol. 2011;94:126–33.
    Article PubMed CAS Google Scholar
  11. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22:915–31.
    Article PubMed CAS Google Scholar
  12. Kato N, Kitaura J, Doki N, Komeno Y, Watanabe-Okochi N, Togami K, et al. Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models. Blood. 2011;117:221–33.
    Article PubMed CAS Google Scholar
  13. Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, et al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest. 2005;115:919–29.
    PubMed CAS Google Scholar
  14. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA. 2002;99:8283–8.
    Article PubMed CAS Google Scholar
  15. Iwasaki M, Kuwata T, Yamazaki Y, Jenkins NA, Copeland NG, Osato M, et al. Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood. 2005;105:784–93.
    Article PubMed CAS Google Scholar
  16. Ding Y, Harada Y, Imagawa J, Kimura A, Harada H. AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. Blood. 2009;114:5201–5.
    Article PubMed CAS Google Scholar
  17. Shi XB, Xue L, Yang J, Ma AH, Zhao J, Xu M, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci US A. 2007;104:19983–8.
    Article CAS Google Scholar
  18. Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 2009;23:862–76.
    Article PubMed CAS Google Scholar
  19. Xia H, He T, Liu C, Cui Y, Song P, Jin X, et al. MiR-125b expression affects the proliferation and apoptosis of human glioma cells by targeting Bmf. Cell Physiol Biochem. 2009;23:347–58.
    Article PubMed CAS Google Scholar
  20. Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000;7:1063–6.
    Article PubMed CAS Google Scholar
  21. Watanabe-Okochi N, Oki T, Komeno Y, Kato N, Yuji K, Ono R, et al. Possible involvement of RasGRP4 in leukemogenesis. Int J Hematol. 2009;89:470–81.
    Article PubMed CAS Google Scholar
  22. Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T, et al. Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol. 2003;31:1007–14.
    PubMed CAS Google Scholar
  23. Enomoto Y, Yamanishi Y, Izawa K, Kaitani A, Takahashi M, Maehara A, et al. Characterization of leukocyte mono-immunoglobulin-like receptor 7 (LMIR7)/CLM-3 as an activating receptor: its similarities to and differences from LMIR4/CLM-5. J Biol Chem. 2010;285:35274–83.
    Article PubMed CAS Google Scholar
  24. O’Connell RM, Zhao JL, Rao DS. MicroRNA function in myeloid biology. Blood. 2011;118:2960–9.
    Article PubMed Google Scholar

Download references

Acknowledgments

This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan, and was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas, Global COE Program “Center of Education and Research for Advanced Genome-Based Medicine—For personalized medicine and the control of worldwide infectious diseases”, MEXT, Japan, a Grant for Basic and Clinical Research Project from Osaka Cancer Research Foundation 2008, a Research Grant on Priority Areas from Wakayama Medical University 2008, and a grant from the Japan Society for the Promotion of Science (JSPS). This work was performed as part of the Cooperative Research Project of the Institute of Medical Science, Tokyo University. Y. Enomoto is a JSPS research fellow.

Conflict of interest

T.K. serves as a consultant for R&D Systems. The remaining authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
    Yutaka Enomoto, Jiro Kitaura, Naoko Kato, Koutarou Nishimura, Mariko Takahashi & Toshio Kitamura
  2. Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
    Toshio Kitamura
  3. Hematology/Oncology, Wakayama Medical University, 811-1 Kimi-idera, Wakayama, 641-8510, Japan
    Masaya Shimanuki, Hideki Nakakuma & Takashi Sonoki

Authors

  1. Yutaka Enomoto
  2. Jiro Kitaura
  3. Masaya Shimanuki
  4. Naoko Kato
  5. Koutarou Nishimura
  6. Mariko Takahashi
  7. Hideki Nakakuma
  8. Toshio Kitamura
  9. Takashi Sonoki

Corresponding authors

Correspondence toToshio Kitamura or Takashi Sonoki.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12185_2012_1143_MOESM1_ESM.ppt

Supplementary material 1 (PPT 540 kb). Supplemental data include the characterization of peripheral blood cells by FACS 5 weeks after BMT

About this article

Cite this article

Enomoto, Y., Kitaura, J., Shimanuki, M. et al. _MicroRNA_-_125b_-1 accelerates a C-terminal mutant of C/EBPα (C/EBPα-Cm)-induced myeloid leukemia.Int J Hematol 96, 334–341 (2012). https://doi.org/10.1007/s12185-012-1143-5

Download citation

Keywords