Abstract:
:Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.
journal_name
Haematologicajournal_title
Haematologicaauthors
Solimando AG,Da Vià MC,Leone P,Borrelli P,Croci GA,Tabares P,Brandl A,Di Lernia G,Bianchi FP,Tafuri S,Steinbrunn T,Balduini A,Melaccio A,De Summa S,Argentiero A,Rauert-Wunderlich H,Frassanito MA,Ditonno P,Henke E,Kldoi
10.3324/haematol.2019.239913subject
Has Abstractpub_date
2020-04-30 00:00:00eissn
0390-6078issn
1592-8721pii
haematol.2019.239913pub_type
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