Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma.
OBJECTIVE
To determine a "gene/molecular fingerprint" of multiple myeloma endothelial cells and identify vascular mechanisms governing the malignant progression from quiescent monoclonal gammopathy of undetermined significance.


METHODS
Comparative gene expression profiling of multiple myeloma endothelial cells and monoclonal gammopathy of undetermined significance endothelial cells with the Affymetrix U133A Arrays was carried out in patients at diagnosis; expression and function of selective vascular markers was validated by real-time reverse transcriptase-PCR, Western blot, and small interfering RNA analyses.


RESULTS
Twenty-two genes were found differentially expressed (14 down-regulated and eight up-regulated) at relatively high stringency in multiple myeloma endothelial cells compared with monoclonal gammopathy of undetermined significance endothelial cells. Functional annotation revealed a role of these genes in the regulation of extracellular matrix formation and bone remodeling, cell adhesion, chemotaxis, angiogenesis, resistance to apoptosis, and cell-cycle regulation. Validation was focused on six genes (DIRAS3, SERPINF1, SRPX, BNIP3, IER3, and SEPW1) not previously found to be functionally correlated to the overangiogenic phenotype of multiple myeloma endothelial cells in active disease. The small interfering RNA knockdown of BNIP3, IER3, and SEPW1 genes affected critical multiple myeloma endothelial cell functions correlated with the overangiogenic phenotype.


CONCLUSIONS
The distinct endothelial cell gene expression profiles and vascular phenotypes detected in this study may influence remodeling of the bone marrow microenvironment in patients with active multiple myeloma. A better understanding of the linkage between plasma cells and endothelial cells in multiple myeloma could contribute to the molecular classification of the disease and thus pinpoint selective gene targets for more effective antiangiogenic treatments.
Ria
Roberto
R
Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
Todoerti
Katia
K
Berardi
Simona
S
Coluccia
Addolorata Maria Luce
AM
De Luisi
Annunziata
A
Mattioli
Michela
M
Ronchetti
Domenica
D
Morabito
Fortunato
F
Guarini
Attilio
A
Petrucci
Maria Teresa
MT
Dammacco
Franco
F
Ribatti
Domenico
D
Neri
Antonino
A
Vacca
Angelo
A
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism*; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051151:Selenoprotein W / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C090121:BNIP3 protein, human; C099815:IER3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C495240:SELENOW protein, human; D051151:Selenoprotein W