JunB is a key regulator of multiple myeloma bone marrow angiogenesis

• Published in: Leukemia Vol. 35; no. 12; pp. 3509 - 3525
• Main Authors: Fan, Fengjuan, Malvestiti, Stefano, Vallet, Sonia, Lind, Judith, Garcia-Manteiga, Jose Manuel, Morelli, Eugenio, Jiang, Qinyue, Seckinger, Anja, Hose, Dirk, Goldschmidt, Hartmut, Stadlbauer, Andreas, Sun, Chunyan, Mei, Heng, Pecherstorfer, Martin, Bakiri, Latifa, Wagner, Erwin F., Tonon, Giovanni, Sattler, Martin, Hu, Yu, Tassone, Pierfrancesco, Jaeger, Dirk, Podar, Klaus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2021; Nature Publishing Group
• Subjects: 101/1; 13/109; 13/89; 14/63; 38/91; 45/77; 631/67/1990/804; 631/80/86; 64/60; 82/51; 96/106; 96/109; 96/21; 96/44; 96/95; Activator protein 1; Angiogenesis; Animal models; Animals; Bone marrow; Bone Marrow - blood supply; Bone Marrow - metabolism; Bone Marrow - pathology; Cancer Research; Cell culture; Cell Line, Tumor; Cell survival; Critical Care Medicine; Development and progression; Drug resistance; Female; Genetic aspects; Health aspects; Hematology; Heterografts; Humans; Hypoxia; Hypoxia-inducible factor 1a; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Intensive; Interleukin-6 - metabolism; Internal Medicine; JunB protein; Medical prognosis; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Microenvironments; Multiple myeloma; Multiple Myeloma - blood supply; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neovascularization; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Physiological aspects; Primary Cell Culture; Statistical analysis; Three dimensional models; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor B - metabolism; Xenografts; Xenotransplantation; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01271-9

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.