JunB is a key regulator of multiple myeloma bone marrow angiogenesis

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

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.

Highlights

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by excess clonal proliferation of malignant plasma cells within the bone marrow (BM), renal disease, immunodeficiency, and osteolytic bone lesions
JunB expression correlates with expression profiles of angiogenic factors in MM cells To investigate whether JunB affects production and secretion of AFs by MM cells and thereby BM angiogenesis, we first performed a comparative supervised analysis of JunB and AFs in healthy donors versus Monoclonal Gammopathy of Unknown Significance (MGUS) and MM samples utilizing publicly available datasets GSE5900 and GSE2658 (n = 625) [24, 25]
Our analysis shows a gradual increase of mRNA levels of AFs VEGF, VEGFB, IGF1, PIGF, HGF, CTGF, TGFB1, IL6, and IL15, along with mRNA levels of JunB from healthy donors to MGUS and MM (Supplementary Fig. 1)

Summary

Introduction

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by excess clonal proliferation of malignant plasma cells within the bone marrow (BM), renal disease, immunodeficiency, and osteolytic bone lesions. Increasing BM angiogenesis parallels disease transition from Monoclonal Gammopathy of Unknown Significance (MGUS) to MM, correlates with MM progression and poor prognosis [2, 5, 6], and decreases with successful anti-MM treatment [6,7,8,9]. Based on the antiangiogenic activity of thalidomide and the discovery that MVD plays a key role in MM pathogenesis, thalidomide was used empirically to treat MM patients in the late 1990s. Similar to thalidomide and its derivates, the immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) mediate anti-MM activity, at least in part, via inhibition of BM angiogenesis [17]. The identification of novel targets and the development of derived efficient anti-MM agents are needed

Methods

Results

Conclusion