Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 Mar 2024
15 Mar 2024
Historique:
received:
30
06
2023
revised:
14
11
2023
accepted:
11
01
2024
medline:
18
3
2024
pubmed:
17
1
2024
entrez:
17
1
2024
Statut:
ppublish
Résumé
Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.
Identifiants
pubmed: 38231476
pii: 733403
doi: 10.1158/0008-5472.CAN-23-1950
pmc: PMC10940855
doi:
Substances chimiques
Ephrin-B2
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Receptor, EphB4
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
919-934Subventions
Organisme : NIAID NIH HHS
ID : U01 AI156922
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262794
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA245483
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL086998
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001881
Pays : United States
Informations de copyright
©2024 The Authors; Published by the American Association for Cancer Research.
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