Proteomic analysis of waldenstrom macroglobulinemia.
To better understand the molecular changes that occur in Waldenstrom macroglobulinemia (WM), we employed antibody-based protein microarrays to compare patterns of protein expression between untreated WM and normal bone marrow controls. Protein expression was defined as a >2-fold or 1.3-fold change in at least 67% of the tumor samples. Proteins up-regulated by >2-fold included Ras family proteins, such as Rab-4 and p62DOK, and Rho family proteins, such as CDC42GAP and ROKalpha. Other proteins up-regulated by >1.3-fold included cyclin-dependent kinases, apoptosis regulators, and histone deacetylases (HDAC). We then compared the samples of patients with symptomatic and asymptomatic WM and showed similar protein expression signatures, indicating that the dysregulation of signaling pathways occurs early in the disease course. Three proteins were different by >2-fold in symptomatic versus asymptomatic, including the heat shock protein HSP90. Elevated protein expression was confirmed by immunohistochemistry and immunoblotting. Functional significance was validated by the induction of apoptosis and inhibition of proliferation using specific HDAC and HSP90 inhibitors. This study, therefore, identifies, for the first time, multiple novel proteins that are dysregulated in WM, which both enhance our understanding of disease pathogenesis and represent targets of novel therapeutics.
Hatjiharissi
Evdoxia
E
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Ngo
Hai
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Leontovich
Alexey A
AA
Leleu
Xavier
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Timm
Michael
M
Melhem
Mona
M
George
Diane
D
Lu
Ganwei
G
Ghobrial
Joanna
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Alsayed
Yazan
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Zeismer
Steven
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Cabanela
Miguel
M
Nehme
Alex
A
Jia
Xiaoying
X
Moreau
Anne Sophie
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Treon
Steven P
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Fonseca
Rafael
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Gertz
Morie A
MA
Anderson
Kenneth C
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Witzig
Thomas E
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Ghobrial
Irene M
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D000368:Aged; D017209:Apoptosis / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000378:metabolism; D040901:Proteomics; D015203:Reproducibility of Results; D008258:Waldenstrom Macroglobulinemia / Q000378:metabolism* / Q000473:pathology
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; C012589:trichostatin A; C112765:tanespimycin