TY - JOUR
T1 - Targeting of CD38 by the tumor suppressor miR-26a serves as a novel potential therapeutic agent in multiple myeloma
AU - Hu, Yi
AU - Liu, Huimin
AU - Fang, Chuanfeng
AU - Li, Chen
AU - Xhyliu, Fjorela
AU - Dysert, Hayley
AU - Bodo, Juraj
AU - Habermehl, Gabriel
AU - Russell, Benjamin E.
AU - Li, Wenjun
AU - Chappell, Marcia
AU - Jiang, Xiaofeng
AU - Ondrejka, Sarah L.
AU - Hsi, Eric D.
AU - Maciejewski, Jaroslaw P.
AU - Yi, Qing
AU - Anderson, Kenneth C.
AU - Munshi, Nikhil C.
AU - Ao, Geyou
AU - Valent, Jason N.
AU - Lin, Jianhong
AU - Zhao, Jianjun
N1 - ©2020 American Association for Cancer Research.
PY - 2020/5/15
Y1 - 2020/5/15
N2 - Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a
in vitro and
in vivo. miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. SIGNIFICANCE: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma.
AB - Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a
in vitro and
in vivo. miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. SIGNIFICANCE: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma.
KW - ADP-ribosyl Cyclase 1/genetics
KW - Animals
KW - Antibodies, Monoclonal/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Antineoplastic Agents, Immunological/pharmacology
KW - Apoptosis/drug effects
KW - Cell Movement/drug effects
KW - Cell Proliferation/drug effects
KW - Drug Resistance, Neoplasm/genetics
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Heterografts
KW - Humans
KW - Mice
KW - MicroRNAs/genetics
KW - Multiple Myeloma/genetics
UR - http://www.scopus.com/inward/record.url?scp=85084943380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084943380&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-1077
DO - 10.1158/0008-5472.CAN-19-1077
M3 - Article
C2 - 32193289
AN - SCOPUS:85084943380
SN - 0008-5472
VL - 80
SP - 2031
EP - 2044
JO - Cancer research
JF - Cancer research
IS - 10
ER -