1. Academic Validation
  2. Inhibitory effect of the substance P and its derivative on erythropoietin-independent growth of erythroid progenitors in polycythemia vera

Inhibitory effect of the substance P and its derivative on erythropoietin-independent growth of erythroid progenitors in polycythemia vera

  • Leuk Res. 2008 May;32(5):743-54. doi: 10.1016/j.leukres.2007.09.011.
Christelle Le Gall 1 Jean-Christophe Ianotto Elisabeth Hardy Valérie Ugo Jean-Richard Eveillard Françoise Ngo-Sack Pascal Bourquard Patrick Morice Christian Berthou
Affiliations

Affiliation

  • 1 Laboratoire de Thérapie Cellulaire et d'Immuno-Biologie du Cancer, EA 2216-CHU de Brest-Hôpital Morvan, 29609 Brest, France. christelle_legall@hotmail.com
Abstract

Regulation of normal hematopoiesis by neuropeptide substance P (SP) and its amino terminal fragment, SP(1-4), has been reported. Endogenous erythroid colony (EEC) formation without erythropoietin is characteristic of polycythemia vera (PV), a chronic myeloproliferative disorder. We investigated the effect(s) of SP and SP(1-4) on EEC formation from PV BM mononuclear cells (BMMCs) and purified CD36+ erythroid progenitors. We found a potent in vitro inhibitory effect of SP and SP(1-4) on PV EEC formation for both BMMCs and CD36+ erythroid progenitors. The influence of SP and SP(1-4) on PV progenitor erythroid differentiation and cell viability was also investigated, and the impact of neurokinin receptors and G proteins in the inhibition were analyzed by quantitative PCR and with specific inhibitors. This progenitor inhibition was: (1) not mediated by accessory cells; (2) characterized by an increase in cell death and inhibition of the EPOindependent terminal erythroid differentiation; and (3) not mediated by the same Neurokinin Receptor. NK-1R and NK-2R antagonists completely abrogated the SP inhibitory effect but not SP(1-4)-induced inhibition. Furthermore, the truncated form of the NK-1R was predominant over the full-length mRNA and could mediated the SP inhibitory effect on PV CD36+ erythroid progenitors. Different G proteins were also implicated according to the erythroid differentiation stage of the PV cells. The observation of an inhibitory effect of SP and its related peptide, SP(1-4), on PV EEC formation at physiological concentrations (10-8M) suggests that neuropeptides represent a way to downregulate pathologic expansion of PV progenitors.

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