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.
