Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.
The transformation from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is thought to be associated with changes in immune processes. We have therefore used serologic analysis of recombinant cDNA expression library to screen the sera of MGUS patients to identify tumor-associated antigens. A total of 10 antigens were identified, with specific antibody responses in MGUS. Responses appeared to be directed against intracellular proteins involved in cellular functions, such as apoptosis (SON, IFT57/HIPPI), DNA and RNA binding (ZNF292, GPATCH4), signal transduction regulators (AKAP11), transcriptional corepressor (IRF2BP2), developmental proteins (OFD1), and proteins of the ubiquitin-proteasome pathway (PSMC1). Importantly, the gene responsible for the oral-facial-digital type I syndrome (OFD1) had response in 6 of 29 (20.6%) MGUS patients but 0 of 11 newly diagnosed MM patients. Interestingly, 3 of 11 (27.2%) MM patients after autologous stem cell transplantations showed responses to OFD1. We have confirmed T-cell responses against OFD1 in MGUS and observed down-regulation of GLI1/PTCH1 and p-beta-catenin after OFD1 knock-down with specific siRNA, suggesting its functional role in the regulation of Hh and Wnt pathways. These findings demonstrate OFD1 as an important immune target and highlight its possible role in signal transduction and tumorigenesis in MGUS and MM.
Blotta
Simona
S
Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Tassone
Pierfrancesco
P
Prabhala
Rao H
RH
Tagliaferri
Piersandro
P
Cervi
David
D
Amin
Samir
S
Jakubikova
Jana
J
Tai
Yu-Tzu
YT
Podar
Klaus
K
Mitsiades
Constantine S
CS
Zullo
Alessandro
A
Franco
Brunella
B
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D010265:Paraproteinemias / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors; D014182:Transplantation, Autologous; D051176:beta Catenin / Q000235:genetics / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C475082:IRF2BP2 protein, human; D009687:Nuclear Proteins; C115130:OFD1 protein, human; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D051176:beta Catenin