Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.

Autor:	Sasine JP; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.; Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California.; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California., Kozlova NY; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California., Valicente L; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California., Dukov J; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California., Tran DH; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California., Himburg HA; Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin., Kumar S; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California., Khorsandi S; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Chan A; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Grohe S; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Li M; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California., Kan J; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California., Sehl ME; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California., Schiller GJ; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California., Reinhardt B; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Singh BK; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California., Ho R; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California., Yue P; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Pasquale EB; Sanford Burnham Prebys Medical Discovery Institute, San Diego, California., Chute JP; Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.; Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California.; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Mar 15; Vol. 84 (6), pp. 919-934.
DOI:	10.1158/0008-5472.CAN-23-1950
Abstrakt:	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. Significance: 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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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