Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease.

Juilette Berger (1) , Séverine Lecourt (2) , Valérie Vanneaux (2) , Chantal Rapatel (1) , Stéphane Boisgard (3) , Catherine Caillaud (4) , Nathalie Boiret-Dupré (1) , Jean-Pierre Marolleau (5) , Jerome Larghero (2) , Christine Chomienne (6) , Marc G Berger (1)

1 Hematologie (Biologie)
2 Unité de Thérapie Cellulaire
3 Orthopédie, Traumatologie et Chirurgie Reconstructive
4 Laboratoire de Génétique Métabolique
5 Service clinique des Maladies du Sang
6 Hématologie -Immunologie -Cibles thérapeutiques

One of the cardinal symptoms of type 1 Gaucher Disease (GD) is cytopenia, usually explained by bone marrow (BM) infiltration by Gaucher cells and hypersplenism. However, some cases of cytopenia in splenectomised or treated patients suggest possible other mechanisms. To evaluate intra-cellular glucocerebrosidase (GlcC) activity in immature progenitors and to prove the conduritol B epoxide (CBE)-induced inhibition of the enzyme, we used an adapted flow cytometry technique before assessing the direct effect of GlcC deficiency in functional assays. Among haematopoietic cells from healthy donors, monocytes showed the highest GlcC activity but we demonstrated that immature CD34+ and mesenchymal cells have significant GlcC activity. CBE greatly inhibited the enzyme activity of all cell categories. GlcC-deficient CD34+ cells showed impaired ability to proliferate and differentiate in the expansion assay and had lower frequency of BFU-E, CFU-G and CFU-M progenitors, but the effect of GlcC deficiency on CFU-Mk lineage was not significant. GlcC deficiency strongly impaired primitive haematopoiesis in long-term culture. Furthermore, GlcC deficiency progressively impaired proliferation of mesenchymal progenitors. These data suggest an intrinsic effect of GlcC deficiency on BM immature cells that supplements the pathophysiology of GD and opens new perspectives of therapeutic approach.

Mots clés: Medicine

Juilette Berger, Séverine Lecourt, Valérie Vanneaux, Chantal Rapatel, Stéphane Boisgard, et al.. Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease.. British Journal of Haematology, 2010, ⟨10.1111/j.1365-2141.2010.08214.x⟩. ⟨hal-00552595⟩