JunB is a key regulator of multiple myeloma bone marrow angiogenesis

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 TassoneDirk Jaeger, Klaus Podar

Research output: Journal article (peer-reviewed)Journal article

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3509-3525
Number of pages17
JournalLeukemia
Volume35
Issue number12
DOIs
Publication statusPublished - Dec 2021

Keywords

  • Animals
  • Bone Marrow/blood supply
  • Cell Line, Tumor
  • Female
  • Heterografts
  • Humans
  • Insulin-Like Growth Factor I/metabolism
  • Interleukin-6/metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Multiple Myeloma/blood supply
  • Neovascularization, Pathologic/genetics
  • Primary Cell Culture
  • Transcription Factors/genetics
  • Vascular Endothelial Growth Factor A/metabolism
  • Vascular Endothelial Growth Factor B/metabolism

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