Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis

Author:

Sasine Joshua P.1234ORCID,Kozlova Natalia Y.12ORCID,Valicente Lisa12ORCID,Dukov Jennifer12ORCID,Tran Dana H.12ORCID,Himburg Heather A.5ORCID,Kumar Sanjeev4ORCID,Khorsandi Sarah1ORCID,Chan Aldi1ORCID,Grohe Samantha1ORCID,Li Michelle6ORCID,Kan Jenny6ORCID,Sehl Mary E.6ORCID,Schiller Gary J.6ORCID,Reinhardt Bryanna1ORCID,Singh Brijesh Kumar7ORCID,Ho Ritchie7ORCID,Yue Peibin1ORCID,Pasquale Elena B.8ORCID,Chute John P.1234ORCID

Affiliation:

1. 1Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

2. 2Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.

3. 3Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California.

4. 4Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.

5. 5Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

6. 6Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California.

7. 7Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California.

8. 8Sanford Burnham Prebys Medical Discovery Institute, San Diego, California.

Abstract

Abstract 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.

Funder

National Institute of Allergy and Infectious Diseases

National Heart, Lung, and Blood Institute

National Cancer Institute

National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

Reference75 articles.

1. Surveillance Epidemiology and End Results (SEER) Program (https://seer.cancer.gov/) SEER*Stat Database: Populations - Total U.S. (1969–2014) <csingle ages to 85+, Katrina/Rita Adjustment>- linked to county attributes - Total U.S., 1969–2014 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch;Surveillance Epidemiology and End Results (SEER) Program,2015

2. 2016 US lymphoid malignancy statistics by World Health Organization subtypes;Teras;CA Cancer J Clin,2016

3. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion;Abe;Blood,2004

4. Multiple myeloma as a model for the role of bone marrow niches in the control of angiogenesis;Ribatti;Int Rev Cell Mol Biol,2015

5. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression;Roccaro;J Clin Invest,2013

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