Skip to main content
SpringerLink
Log in

A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report

  • Report
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APL-derived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA-induced gene transcription, regulates the expression of miR-142-3p in APL-derived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p.

Methods

ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT-PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1.

Results

We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist-induced increases in both PU.1 and Vav1.

Conclusions

Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. F. Lo-Coco, E. Ammatuna, The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematology Am. Soc. Hematol. Educ. Program 2006, 156–161 (2006). doi:10.1182/asheducation-2006.1.156

  2. T. M. Kadia, F. Ravandi, S. O’Brien, J. Cortes, H. M. Kantarjian, Progress in acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 15, 139–151 (2015). doi:10.1016/j.clml.2014.08.006

    Article  PubMed  Google Scholar 

  3. M. A. Gakidis, X. Cullere, T. Olson, J. L. Wilsbacher, B. Zhang, S. L. Moores, K. Ley, W. Swat, T. Mayadas, J. S. Brugge, Vav GEFs are required for beta2 integrin-dependent functions of neutrophils. J. Cell Biol. 166, 273–282 (2004). doi:10.1083/jcb.200404166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. V. L. Tybulewicz, Vav-family proteins in T-cell signaling. Curr. Opin. Immunol. 17, 267–274 (2005). doi:10.1016/j.coi.2005.04.003

    Article  CAS  PubMed  Google Scholar 

  5. V. Bertagnolo, F. Brugnoli, S. Grassilli, E. Nika, S. Capitani, Vav1 in differentiation of tumoral promyelocytes. Cell. Signal. 24, 612–620 (2012). doi:10.1016/j.cellsig.2011.11.017

    Article  CAS  PubMed  Google Scholar 

  6. V. Bertagnolo, S. Grassilli, A. Petretto, E. Lambertini, L. Astati, M. Bruschi, F. Brugnoli, E. Nika, G. Candiano, R. Piva, S. Capitani, Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes. J. Proteomics 75, 398–409 (2011). doi:10.1016/j.jprot.2011.08.005

    Article  CAS  PubMed  Google Scholar 

  7. M. Houlard, R. Arudchandran, F. Regnier-Ricard, A. Germani, S. Gisselbrecht, U. Blank, J. Rivera, N. Varin-Blank, Vav1 is a component of transcriptionally active complexes. J. Exp. Med. 195, 1115–1127 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. H. Schneider, C. E. Rudd, CD28 and Grb-2, relative to Gads or Grap, preferentially co-operate with Vav1 in the activation of NFAT/AP-1 transcription. Biochem. Biophys. Res. Comm. 369, 616–621 (2008). doi:10.1016/j.bbrc.2008.02.068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. F. Brugnoli, E. Lambertini, N. Varin-Blank, R. Piva, M. Marchisio, S. Grassilli, S. Miscia, S. Capitani, V. Bertagnolo, Vav1 and PU.1 are recruited to the CD11b promoter in APL-derived promyelocytes: role of Vav1 in modulating PU.1-containing complexes during ATRA-induced differentiation. Exp. Cell Res. 316, 38–47 (2010). doi:10.1016/j.yexcr.2009.09.004

    Article  CAS  PubMed  Google Scholar 

  10. P. Burda, P. Laslo, T. Stopka, The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis. Leukemia 24, 1249–1257 (2010). doi:10.1038/leu.2010.104

    Article  CAS  PubMed  Google Scholar 

  11. D. J. Denkinger, T. Q. Lambrecht, A. M. Cushman-Vokoun, R. S. Kawahara, PU.1 regulates the expression of the vav proto-oncogene. J. Cell. Biochem. 84, 772–783 (2002)

    Article  PubMed  Google Scholar 

  12. P. Kastner, S. Chan, PU.1: a crucial and versatile player in hematopoiesis and leukemia. Int. J. Biochem. Cell Biol. 40, 22–27 (2008). doi:10.1016/j.biocel.2007.01.026

    Article  CAS  PubMed  Google Scholar 

  13. M. F. Alemdehy, S. J. Erkeland, MicroRNAs: key players of normal and malignant myelopoiesis. Curr. Opin. Hematol. 19, 261–267 (2012). doi:10.1097/MOH.0b013e328353d4e9

    Article  CAS  PubMed  Google Scholar 

  14. M. L. De Marchis, M. Ballarino, B. Salvatori, M. C. Puzzolo, I. Bozzoni, A. Fatica, A new molecular network comprising PU.1, interferon regulatory factor proteins and miR-342 stimulates ATRA-mediated granulocytic differentiation of acute promyelocytic leukemia cells. Leukemia 23, 856–862 (2009). doi:10.1038/leu.2008.372

    Article  CAS  PubMed  Google Scholar 

  15. Y. Sun, J. Sun, T. Tomomi, E. Nieves, N. Mathewson, H. Tamaki, R. Evers, P. Reddy, PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell–specific expression and modulation of IL-6. J. Immunol. 190, 4005–4013 (2013). doi:10.4049/jimmunol.1202911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. F. Wang, X. S. Wang, G. H. Yang, P. F. Zhai, Z. Xiao, L. Y. Xia, L. R. Chen, Y. Wang, X. Z. Wang, L. X. Bi, N. Liu, Y. Yu, D. Gao, B. T. Huang, J. Wang, D. B. Zhou, J. N. Gong, H. L. Zhao, X. H. Bi, J. Yu, J. W. Zhang, miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia. Mol. Biol. Rep. 39, 2713–2722 (2012). doi:10.1007/s11033-011-1026-5

    Article  CAS  PubMed  Google Scholar 

  17. X. S. Wang, J. N. Gong, J. Yu, F. Wang, X. H. Zhang, X. L. Yin, Z. Q. Tan, Z. M. Luo, G. H. Yang, C. Shen, J. W. Zhang, MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood 119, 4992–5004 (2012). doi:10.1182/blood-2011-10-385716

    Article  CAS  PubMed  Google Scholar 

  18. V. Bertagnolo, F. Brugnoli, C. Mischiati, A. Sereni, A. Bavelloni, C. Carini, S. Capitani, Vav promotes differentiation of human tumoral myeloid precursors. Exp. Cell Res. 306, 56–63 (2005). doi:10.1016/j.yexcr.2004.12.001

    Article  CAS  PubMed  Google Scholar 

  19. E. Lambertini, L. Penolazzi, C. Morganti, G. Lisignoli, N. Zini, M. Angelozzi, M. Bonora, L. Ferroni, P. Pinton, B. Zavan, R. Piva, Osteogenic differentiation of human MSCs: specific occupancy of the mitochondrial DNA by NFATc1 transcription factor. Int. J. Biochem. Cell Biol. 64, 212–219 (2015). doi:10.1016/j.biocel.2015.04.011

    Article  CAS  PubMed  Google Scholar 

  20. E. Prodromaki, A. Korpetinou, E. Giannopoulou, E. Vlotinou, M. Chatziathanasiadou, N. I. Papachristou, C. D. Scopa, H. Papadaki, H. P. Kalofonos, D. J. Papachristou, Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas. Cell. Oncol. 38, 307–317 (2015). doi:10.1007/s13402-015-0231-y

    Article  CAS  Google Scholar 

  21. C. Yu, M. Wang, Z. Li, J. Xiao, F. Peng, X. Guo, Y. Deng, J. Jiang, C. Sun, MicroRNA-138-5p regulates pancreatic cancer cell growth through targeting FOXC1. Cell. Oncol. 38, 173–181 (2015). doi:10.1007/s13402-014-0200-x

    Article  Google Scholar 

  22. E. Yiannakopoulou, Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents--implications for cancer treatment and chemoprevention. Cell. Oncol. 37, 167–178 (2014). doi:10.1007/s13402-014-0175-7

    Article  CAS  Google Scholar 

  23. M. Shahjahani, J. Mohammadiasl, F. Noroozi, M. Seghatoleslami, S. Shahrabi, F. Saba, N. Saki, Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis. Cell. Oncol. 38, 93–109 (2015). doi:10.1007/s13402-014-0215-3

    Article  CAS  Google Scholar 

  24. G. Marcucci, K. Mrozek, M. D. Radmacher, R. Garzon, C. D. Bloomfield, The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 117, 1121–1129 (2011). doi:10.1182/blood-2010-09-191312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Y. Pan, M. Meng, G. Zhang, H. Han, Q. Zhou, Oncogenic microRNAs in the genesis of leukemia and lymphoma. Curr. Pharm. Des. 20, 5260–5267 (2014)

    Article  CAS  PubMed  Google Scholar 

  26. D. Schotte, R. Pieters, M. L. Den Boer, MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 26, 1–12 (2012). doi:10.1038/leu.2011.151

    Article  CAS  PubMed  Google Scholar 

  27. B. Huang, J. Zhao, Z. Lei, S. Shen, D. Li, G. X. Shen, G. M. Zhang, Z. H. Feng, miR-142-3p restricts cAMP production in CD4+CD25- T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 10, 180–185 (2009). doi:10.1038/embor.2008.224

    Article  CAS  PubMed  Google Scholar 

  28. B. Lagrange, R. Z. Martin, N. Droin, R. Aucagne, J. Paggetti, A. Largeot, R. Itzykson, E. Solary, L. Delva, J. N. Bastie, A role for miR-142-3p in colony-stimulating factor 1-induced monocyte differentiation into macrophages. Biochim. Biophys. Acta 1833, 1936–1946 (2013). doi:10.1016/j.bbamcr.2013.04.007

    Article  CAS  PubMed  Google Scholar 

  29. W. Sun, W. Shen, S. Yang, F. Hu, H. Li, T. H. Zhu, miR-223 and miR-142 attenuate hematopoietic cell proliferation, and miR-223 positively regulates miR-142 through LMO2 isoforms and CEBP-β. Cell Res. 20, 1158–1169 (2010). doi:10.1038/cr.2010.134

    Article  PubMed  Google Scholar 

  30. B. U. Mueller, T. Pabst, J. Fos, V. Petkovic, M. F. Fey, N. Asou, U. Buergi, D. G. Tenen, ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 107, 3330–3338 (2006). doi:10.1182/blood-2005-07-3068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. P. Gupta, G. U. Gurudutta, D. Saluja, R. P. Tripathi, PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis. J. Cell. Mol. Med. 13, 4349–4363 (2009). doi:10.1111/j.1582-4934.2009.00757.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. U. Bissels, S. Wild, S. Tomiuk, M. Hafner, H. Scheel, A. Mihailovic, Y. H. Choi, T. Tuschl, A. Bosio, Combined characterization of microRNA and mRNA profiles delineates early differentiation pathways of CD133+ and CD34+ hematopoietic stem and progenitor cells. Stem Cells 29, 847–857 (2011). doi:10.1002/stem.627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Y. Sun, S. Varambally, C. A. Maher, Q. Cao, P. Chockley, T. Toubai, C. Malter, E. Nieves, I. Tawara, Y. Wang, P. A. Ward, A. Chinnaiyan, P. Reddy, Targeting of microRNA-142-3p in dendritic cells regulates endotoxin induced mortality. Blood 117, 6172–6183 (2011). doi:10.1182/blood-2010-12-325647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. L. Wu, C. Cai, X. Wang, M. Liu, X. Li, H. Tang, MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. FEBS Lett. 585, 1322–1330 (2011). doi:10.1016/j.febslet.2011.03.067

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Italian MIUR (PRIN 200938XJLA_003, FIRB RBAP10Z7FS_002) to S.C and from the University of Ferrara (Italy) to V.B.

Author information

Authors and Affiliations

  1. Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy

    Silvia Grassilli, Ervin Nika, Federica Brugnoli, Silvano Capitani & Valeria Bertagnolo

  2. Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121, Ferrara, Italy

    Elisabetta Lambertini & Roberta Piva

  3. LTTA, University of Ferrara, 44121, Ferrara, Italy

    Silvano Capitani

Authors
  1. Silvia Grassilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ervin Nika
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisabetta Lambertini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federica Brugnoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberta Piva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silvano Capitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Valeria Bertagnolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valeria Bertagnolo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Silvia Grassilli and Ervin Nika are equal first authors.

Silvano Capitani and Valeria Bertagnolo are equal last authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grassilli, S., Nika, E., Lambertini, E. et al. A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report. Cell Oncol. 39, 483–489 (2016). https://doi.org/10.1007/s13402-016-0292-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-016-0292-6

Keywords

Search

Navigation