Phosphatidylinositol 3-kinases are involved in the all-trans retinoic acid-induced upregulation of CD38 antigen on human haematopoietic cells.
All-trans retinoic acid (ATRA) is a specific inducer of CD38 antigen on marrow CD34+ cells as well as on blast cells in acute promyelocytic and myeloblastic leukaemia. The CD38 antigen contributes to the control of blast cell proliferation, and the upregulation of CD38 might constitute an element in the pathogenesis of retinoic acid syndrome. The aim of this study was to determine whether phosphoinositide 3-kinase (PI3-K) is involved in the modification of CD38 antigen expression on myeloid cells, as PI3-K plays a major role in the ATRA-induced granulocytic differentiation of HL-60 cells. We evaluated the effects of PI3-K inhibitors (wortmannin and LY294002) on the levels of CD38 antigen and mRNA in HL-60 and normal marrow CD34+ cells exposed to ATRA (1 micromol/l). The inhibitors prevented increase in CD38 mRNA expression and the overexpression of membrane CD38 antigen, without modification of the cytoplasmic level of this antigen. Interestingly, PI3-K activity was also necessary for CD38 expression on normal marrow CD34+ cells and for the ATRA-induced upregulation of CD157, a CD38-related antigen. In conclusion, PI3-K activity plays an essential role in the regulation of CD38 expression on human haematopoietic cells, and might constitute an interesting therapeutic target in haematological disorders involving CD38 overexpression.
Lewandowski
Daniel
D
UPRES-EA 3249 'Haematopoietic cells, Haemostasis and Transplantation', Faculty of Medicine, University Hospital Bretonneau, boulevard Tonnellé, 37044 Tours Cedex, France.
Linassier
Claude
C
Iochmann
Sophie
S
Degenne
Michel
M
Domenech
Jorge
J
Colombat
Philippe
P
Binet
Christian
C
Hérault
Olivier
O
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000730:Androstadienes / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins; D009025:Morpholines / Q000494:pharmacology; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation; D000077191:Wortmannin
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000730:Androstadienes; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D009025:Morpholines; D009244:NAD+ Nucleosidase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014212:Tretinoin; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C498154:CD38 protein, human