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| Leukemia. 2021 May 18. doi: 10.1038/s41375-021-01271-9. pii: 10.1038/s41375-021-01271-9 |
| JunB is a key regulator of multiple myeloma bone marrow angiogenesis. |
| Fan F1, Malvestiti S2, Vallet S3, Lind J4, Garcia-Manteiga JM5, Morelli E6, Jiang Q7, Seckinger A8, Hose D9, Goldschmidt H10, Stadlbauer A11, Sun C12, Mei H13, Pecherstorfer M14, Bakiri L15, Wagner EF16, Tonon G17, Sattler M18, Hu Y19, Tassone P20, Jaeger D21, Podar K22 |
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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. |
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Publikations ID: 34007044 Quelle: öffnen |
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