Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia.
Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes ("physiologic" UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)-processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19(+) cells from patients with WM with an inhibitory concentration (IC(50)) of 0.5 microg/mL to 1 microg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.
Leleu
Xavier
X
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Xu
Lian
L
Jia
Xiaoying
X
Sacco
Antonio
A
Farag
Mena
M
Hunter
Zachary R
ZR
Moreau
Anne-Sophie
AS
Ngo
Hai T
HT
Hatjiharissi
Evdoxia
E
Ho
Allen W
AW
Santos
Daniel D
DD
Adamia
Sofia
S
O'Connor
Kelly
K
Ciccarelli
Bryan
B
Soumerai
Jacob
J
Manning
Robert J
RJ
Patterson
Christopher J
CJ
Roccaro
Aldo M
AM
Ghobrial
Irene M
IM
Treon
Steven P
SP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D017510:Protein Folding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological; D014415:Tunicamycin / Q000494:pharmacology*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents; D014415:Tunicamycin