Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma.
Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.
Institut National de la Santé et de la Recherche Médicale, U1037, Toulouse, France. corre.j@chu-toulouse.fr
Jill
J
Corre
Elodie
E
Labat
Nicolas
N
Espagnolle
Benjamin
B
Hébraud
Hervé
H
Avet-Loiseau
Murielle
M
Roussel
Anne
A
Huynh
Mélanie
M
Gadelorge
Pierre
P
Cordelier
Bernard
B
Klein
Philippe
P
Moreau
Thierry
T
Facon
Jean-Jacques
JJ
Fournié
Michel
M
Attal
Philippe
P
Bourin
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood / Q000378:metabolism*; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D011719:Pyrazines / Q000627:therapeutic use; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001897:Boronic Acids; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D000077269:Lenalidomide; D008558:Melphalan