CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia.
Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.
Ho
Allen W
AW
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Hatjiharissi
Evdoxia
E
Ciccarelli
Bryan T
BT
Branagan
Andrew R
AR
Hunter
Zachary R
ZR
Leleu
Xavier
X
Tournilhac
Olivier
O
Xu
Lian
L
O'Connor
Kelly
K
Manning
Robert J
RJ
Santos
Daniel Ditzel
DD
Chemaly
Mariana
M
Patterson
Christopher J
CJ
Soumerai
Jacob D
JD
Munshi
Nikhil C
NC
McEarchern
Julie A
JA
Law
Che-Leung
CL
Grewal
Iqbal S
IS
Treon
Steven P
SP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D053282:CD27 Ligand / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D047368:Tumor Burden; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism* / Q000502:physiology; D008258:Waldenstrom Macroglobulinemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D053282:CD27 Ligand; C505771:CD70 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7