Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7.
Animals
Antibodies, Monoclonal, Humanized
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Proliferation
/ drug effects
Humans
Lenalidomide
/ pharmacology
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma
/ metabolism
Signaling Lymphocytic Activation Molecule Family
/ metabolism
Thalidomide
/ analogs & derivatives
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
14
11
2018
accepted:
04
06
2019
revised:
24
04
2019
pubmed:
31
7
2019
medline:
2
7
2020
entrez:
31
7
2019
Statut:
ppublish
Résumé
SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7 gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.
Identifiants
pubmed: 31358854
doi: 10.1038/s41375-019-0525-6
pii: 10.1038/s41375-019-0525-6
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
SLAMF7 protein, human
0
Signaling Lymphocytic Activation Molecule Family
0
elotuzumab
1351PE5UGS
Thalidomide
4Z8R6ORS6L
pomalidomide
D2UX06XLB5
Lenalidomide
F0P408N6V4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
180-195Références
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