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Protein kinase N3 deficiency impedes PI3-kinase pathway-driven leukemogenesis without affecting normal hematopoiesis

Leukemia volume 29, pages 255–258 (2015)Cite this article

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Protein kinase N family genes encode AGC-type serine–threonine kinases (PKN1, PKN2 and PKN3) that interact with Rho family proteins to regulate cytoskeletal organization and gene expression.1, 2, 3 Whereas PKN1 and PKN2 are ubiquitously expressed, PKN3 expression is low in most normal human tissues but high in some malignancies.3 PKN3 catalytic activity is regulated by RhoC and by the PI3-kinase (PI3K) signaling pathway.4,5 PKN3 inactivation inhibits growth of PI3K-driven prostate and breast cancer xenografts.4,5 Its role in hematopoietic malignancies has not yet been described. Since the PI3K pathway is hyper-activated in many types of leukemia,6, 7, 8 PKN3 may be a useful target for treating leukemia patients.

We used genetically engineered mice to test whether Pkn3 regulates normal hematopoiesis and T-cell leukemogenesis in vivo. A conditional Pkn3 allele (Pkn3fl) was generated by flanking exons 2–6 with LoxP sites (Supplementary Figure S1A). Cre-mediated deletion of exons 2–6 caused a frame shift after codon 5 and a premature translational stop signal at codon 20. Germ line-deleted Pkn3−/− mice did not express transcripts from exons 2–6 or the PKN3 protein (Supplementary Figures S1B and C), consistent with our expectation that this deletion yields a null allele. Pkn3−/− mice were born in expected Mendelian ratios. They were viable, fertile and healthy, so Pkn3 is not essential for normal development or homeostasis.

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References

  1. Metzger E, Imhof A, Patel D, Kahl P, Hoffmeyer K, Friedrichs N et al. Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4. Nature 2010; 464: 792–796.

    Article  CAS  PubMed  Google Scholar 

  2. Lachmann S, Jevons A, De Rycker M, Casamassima A, Radtke S, Collazos A et al. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS One 2011; 6: e21732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mukai H . The structure and function of PKN, a protein kinase having a catalytic domain homologous to that of PKC. J Biochem 2003; 133: 17–27.

    Article  CAS  PubMed  Google Scholar 

  4. Leenders F, Mopert K, Schmiedeknecht A, Santel A, Czauderna F, Aleku M et al. PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase. EMBO J 2004; 23: 3303–3313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Unsal-Kacmaz K, Ragunathan S, Rosfjord E, Dann S, Upeslacis E, Grillo M et al. The interaction of PKN3 with RhoC promotes malignant growth. Mol Oncol 2012; 6: 284–298.

    Article  CAS  PubMed  Google Scholar 

  6. Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20: 911–928.

    Article  CAS  PubMed  Google Scholar 

  7. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010; 16: 205–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647–650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203–1210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Homminga I, Pieters R, Langerak AW, de Rooi JJ, Stubbs A, Verstegen M et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell 2011; 19: 484–497.

    Article  CAS  PubMed  Google Scholar 

  11. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–482.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441: 518–522.

    Article  CAS  PubMed  Google Scholar 

  13. Di Cristofano A, Pandolfi PP . The multiple roles of PTEN in tumor suppression. Cell 2000; 100: 387–390.

    Article  CAS  PubMed  Google Scholar 

  14. Magee JA, Ikenoue T, Nakada D, Lee JY, Guan KL, Morrison SJ . Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell 2012; 11: 415–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A Kippel, S Shumway, P Blume-Jensen, N Kohl, G Draetta, T Vogt, G Staples and M Schoor for helpful discussions. A Klippel provided the PKN3 antibody. JAM is a Scholar of the Child Health Research Center at Washington University School of Medicine (K12-HD076224) and the Children’s Discovery Institute of Washington University and St Louis Children’s Hospital. Experiments were initiated in Sean Morrison’s laboratory.

Author Contributions

MK oversaw generation of the Pkn3fl mouse line. MK, BD and TWR performed initial characterization of Pkn3−/− mice (Supplementary Figure S1), participated in the study design and assisted with preparation of the manuscript. JAM designed and performed all experiments with the exception of Supplementary Figure S1, interpreted data and wrote the manuscript. All authors approved the final manuscript.

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Authors and Affiliations

  1. Oncology, Merck Research Laboratories, Boston, MA, USA

    M Kraus & B Dolinski

  2. In vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA

    T W Rosahl

  3. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

    J A Magee

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  1. M Kraus
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  2. B Dolinski
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  4. J A Magee
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Corresponding author

Correspondence to J A Magee.

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Competing interests

Pkn3fl mice were generated by Taconic-Artemis for MK, BD and TWR at Merck & Co., and the mice were subsequently provided to JAM for further analysis. JAM has no conflict of interest to declare.

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Supplementary Information accompanies this paper on the Leukemia website

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Kraus, M., Dolinski, B., Rosahl, T. et al. Protein kinase N3 deficiency impedes PI3-kinase pathway-driven leukemogenesis without affecting normal hematopoiesis. Leukemia 29, 255–258 (2015). https://doi.org/10.1038/leu.2014.278

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