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Fan F, Malvestiti S, Vallet S, et al. JunB is a key regulator of multiple myeloma bone marrow angiogenesis. Leukemia. 2021;35(12):3509-3525doi: 10.1038/s41375-021-01271-9.
Fan, F., Malvestiti, S., Vallet, S., Lind, J., Garcia-Manteiga, J. M., Morelli, E., Jiang, Q., Seckinger, A., Hose, D., Goldschmidt, H., Stadlbauer, A., Sun, C., Mei, H., Pecherstorfer, M., Bakiri, L., Wagner, E. F., Tonon, G., Sattler, M., Hu, Y., Tassone, P., Jaeger, D., & Podar, K. (2021). JunB is a key regulator of multiple myeloma bone marrow angiogenesis. Leukemia, 35(12), 3509-3525. https://doi.org/10.1038/s41375-021-01271-9
Fan, Fengjuan, et al. "JunB is a key regulator of multiple myeloma bone marrow angiogenesis." Leukemia vol. 35,12 (2021): 3509-3525. doi: https://doi.org/10.1038/s41375-021-01271-9
Fan F, Malvestiti S, Vallet S, Lind J, Garcia-Manteiga JM, Morelli E, Jiang Q, Seckinger A, Hose D, Goldschmidt H, Stadlbauer A, Sun C, Mei H, Pecherstorfer M, Bakiri L, Wagner EF, Tonon G, Sattler M, Hu Y, Tassone P, Jaeger D, Podar K. JunB is a key regulator of multiple myeloma bone marrow angiogenesis. Leukemia. 2021 Dec;35(12):3509-3525. doi: 10.1038/s41375-021-01271-9. Epub 2021 May 18. PMID: 34007044; PMCID: PMC8632680.
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Leukemia. 2021 Dec;35(12):3509-3525. doi: 10.1038/s41375-021-01271-9. Epub 2021 May 18.

JunB is a key regulator of multiple myeloma bone marrow angiogenesis.

Leukemia

Fengjuan Fan, Stefano Malvestiti, Sonia Vallet, Judith Lind, Jose Manuel Garcia-Manteiga, Eugenio Morelli, Qinyue Jiang, Anja Seckinger, Dirk Hose, Hartmut Goldschmidt, Andreas Stadlbauer, Chunyan Sun, Heng Mei, Martin Pecherstorfer, Latifa Bakiri, Erwin F Wagner, Giovanni Tonon, Martin Sattler, Yu Hu, Pierfrancesco Tassone, Dirk Jaeger, Klaus Podar

Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  2. Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
  3. Department of Internal Medicine II, University Hospital Krems, Krems an der Donau, Austria.
  4. Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
  5. Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  6. Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Catanzaro, Italy.
  7. Department of Medicine, Harvard Medical School, Boston, MA, USA.
  8. University Hospital Heidelberg, Heidelberg, Germany.
  9. Laboratory of Hematology and Immunology & Laboratory for Myeloma Research, Vrije Universiteit Brussel (VUB) Belgium, Brussels, Belgium.
  10. Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
  11. Institute of Medical Radiology, University Hospital St. Pölten, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
  12. Genes & Disease Group, Department of Dermatology, Medical University of Vienna (MUW), Vienna, Austria.
  13. Genes & Disease Group, Department of Laboratory Medicine, Medical University of Vienna (MUW), Vienna, Austria.
  14. Functional Genomics of Cancer Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  15. Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
  16. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  17. Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. [email protected].
  18. Department of Internal Medicine II, University Hospital Krems, Krems an der Donau, Austria. [email protected].
  19. Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria. [email protected].

PMID: 34007044 PMCID: PMC8632680 DOI: 10.1038/s41375-021-01271-9

Abstract

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.

© 2021. The Author(s).

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