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Acute Leukemias

Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation

Leukemia volume 24, pages 429–437 (2010)Cite this article

Abstract

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight–twenty–one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.

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Acknowledgements

We are grateful to Pier Giuseppe Pelicci for helpful discussions. We thank Francesco Lo Coco (Tor Vergata University, Rome, Italy) and the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto) Acute Leukemia Working Party for AML samples. We are grateful to Manuela Capillo for assistance with mouse models, Giuseppe Ossolengo for the production of anti-PIR antibody, to Elisa Venturini, Luca Rotta and Simone P Minardi for support in microarray experiments and analysis of results with IPA (Ingenuity) software, to Loris Bernard, Laura Tizzoni and Valentina Dall’Olio for support in qPCR experiments and to Ivan Muradore and Simona Ronzoni for FACS analysis. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione CARIPLO to MA.

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Authors and Affiliations

  1. Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy

    S Licciulli, V Cambiaghi, G Scafetta, A M Gruszka & M Alcalay

  2. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Milano, Milan, Italy

    M Alcalay

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  1. S Licciulli
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  2. V Cambiaghi
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  4. A M Gruszka
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  5. M Alcalay
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Correspondence to M Alcalay.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Licciulli, S., Cambiaghi, V., Scafetta, G. et al. Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation. Leukemia 24, 429–437 (2010). https://doi.org/10.1038/leu.2009.247

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