Page 56 - Haematologica May 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1216-1222
Hematopoiesis
Prion protein deficiency impairs hematopoietic stem cell determination and sensitizes myeloid progenitors to irradiation
Capucine Siberchicot,1,2,3,4 Nathalie Gault,1,3,4,5,6 Nathalie Déchamps,1,3,4,6
Vilma Barroca,1,3,4,5,6 Adriano Aguzzi,7 Paul-Henri Roméo,1,3,4,5,6
J. Pablo Radicella,1,2,3,4 Anne Bravard,1,2,3,4,5,6 Jacqueline Bernardino-Sgherri1,2,3,4,5,6
1French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France; 2Laboratory of Research in Genetic Instability (LRIG), 92265 Fontenay-aux-Roses Cedex, France; 3Université Paris-Diderot, Sorbonne Paris Cité, Paris, France; 4Université Paris- Sud, Paris, France; 5Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France; 6Inserm U967, 92265 Fontenay-aux- Roses Cedex, France and 7Institute of Neuropathology, University of Zurich, Zurich, Switzerland
ABSTRACT
Highly conserved among species and expressed in various types of cells, numerous roles have been attributed to the cellular prion pro- tein (PrPC). In hematopoiesis, PrPC regulates hematopoietic stem cell self-renewal but the mechanisms involved in this regulation are unknown. Here we show that PrPC regulates hematopoietic stem cell number during aging and their determination towards myeloid progenitors. Furthermore, PrPC protects myeloid progenitors against the cytotoxic effects of total body irradiation. This radioprotective effect was associated with increased cellular prion mRNA level and with stimulation of the DNA repair activity of the Apurinic/pyrimidinic endonuclease 1, a key enzyme of the base excision repair pathway. Altogether, these results show a previously unappreciated role of PrPC in adult hematopoiesis, and indicate that PrPC-mediated stim- ulation of BER activity might protect hematopoietic progenitors from the cytotoxic effects of total body irradiation.
Introduction
Radiotherapy is commonly used alone or in combination with genotoxic drugs for treatment of numerous solid tumors. Despite progress in its targeting, radiotherapy can be deleterious to two tissues, the gastrointestinal tract and the bone marrow (BM), and can lead to secondary effects commonly defined as Acute Radiation Syndrome.1 Irradiation of the BM damages hematopoietic stem and progenitor cells (HSPC) and perturbs the hematopoietic microenvironment,2,3 resulting in radiation- induced acute myelosuppression4,5 and increased susceptibility to infections.6,7
Numerous types of DNA lesions are induced by cell exposure to ionizing radia- tion. They include base modifications, apurinic/apyrimidic sites (AP sites), and sin- gle- (SSB) and double (DSB)-strand breaks. DSB are the main lesions affecting cell survival. They can arise not only directly by deposition of energy on the DNA, but also as a consequence of the formation of AP sites or SSB.8,9 Indeed, base excision repair (BER) activities, and in particular the processing of abasic sites, have been shown to contribute to radiation-induced DNA damage.10,11
Apurinic/apyrimidic endonuclease-1 (Ape1) is the unique enzyme that converts AP sites into SSB intermediates during BER. Ape1 3’-phosphodieterase and -phos- phate activities (for a review, see Laev et al.12) also contribute to the processing of radiation-induced DNA strand break extremities13 during the single strand break repair pathway (SSBR). Accordingly, protection of neuronal cells from radiation- induced damage requires Ape1.14,15
The cellular prion protein (PrPC) is a highly conserved glycoprotein that, when structurally modified, plays a critical role in the pathogenesis of neurodegenerative
Correspondence:
JACQUELINE BERNARDINO-SGHERRI
jacqueline.bernardino@cea.fr
ANNE BRAVARD
anne.bravard@cea.fr
Received: September 3, 2018. Accepted: July 15, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2018.205716
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