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PLZF-mediated control on c-kit expression in CD34+ cells and early erythropoiesis

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Abstract

The promyelocytic leukemia zinc-finger protein (PLZF) is a transcription factor and c-kit is a receptor tyrosine kinase associated with human disease, particularly in hematopoietic cells. MicroRNAs (miRs) are post-transcriptional regulators of gene expression, and c-kit has been described as a target of miRs-221 and -222 in erythropoiesis. In the present study, we identified c-kit as a target of PLZF in normal and leukemic cells. Particularly, in erythropoietic (E) culture of CD34+ progenitors, PLZF is downregulated, whereas c-kit expression at both the mRNA and protein levels inversely increases during the first days of E differentiation. In functional experiments, PLZF transfection induces c-kit downregulation, inhibits E proliferation and delays differentiation, whereas PLZF knockdown induces opposite effects, independently of miRs-221 and -222 expression. The inverse correlation between PLZF and c-kit expression was found in normal CD34+38+/− hematopoietic progenitor/stem cells and in acute myeloid leukemias of M0/M1 French–American–British subtypes, suggesting that the control of PLZF on c-kit expression may be crucial at the level of the stem cell/progenitor compartment. Altogether, our data indicate a new mechanism of regulation of c-kit expression that involves a transcriptional control by PLZF in CD34+ cells and early erythropoiesis.

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Acknowledgements

We thank Dr F Spadaro, from the Department of Cell Biology and Neuroscience, for her help with confocal microscopy and G Loreto for graphics. This work was supported by institutional grants from the Italian Ministry of Health to UT and CL, from Associazione Italiana per la Ricerca sul Cancro (AIRC) to RF, and from ‘Fondazione Roma’, Rome, Italy to UT.

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  1. I Spinello and M T Quaranta: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    I Spinello, M T Quaranta, L Pasquini, E Pelosi, E Petrucci, A Pagliuca, G Castelli, G Mariani, U Testa & C Labbaye

  2. Division of Hematology, Department of Cellular Biotechnologies and Hematology, ‘Sapienza’ University, Rome, Italy

    D Diverio & R Foà

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  1. I Spinello
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  2. M T Quaranta
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  3. L Pasquini
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  4. E Pelosi
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  5. E Petrucci
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  6. A Pagliuca
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  7. G Castelli
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  9. D Diverio
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  10. R Foà
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  11. U Testa
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  12. C Labbaye
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Correspondence to C Labbaye.

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Spinello, I., Quaranta, M., Pasquini, L. et al. PLZF-mediated control on c-kit expression in CD34+ cells and early erythropoiesis. Oncogene 28, 2276–2288 (2009). https://doi.org/10.1038/onc.2009.87

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  • DOI: https://doi.org/10.1038/onc.2009.87

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