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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3276-3284.
Prepublished online as a Blood First Edition Paper on July 8, 2009; DOI 10.1182/blood-2009-04-219436.
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Submitted April 30, 2009
Accepted June 24, 2009
Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance
Simona Blotta, Pierfrancesco Tassone, Rao H. Prabhala, Piersandro Tagliaferri, David Cervi, Samir Amin, Jana Jakubikova, Yu-Tzu Tai, Klaus Podar, Constantine S. Mitsiades, Alessandro Zullo, Brunella Franco, Kenneth C. Anderson, and Nikhil C. Munshi*
Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, MA, United States
University of "Magna Graecia" and Cancer Center, Catanzaro, Italy
VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
Medical Genetics Department of Pediatrics, Federico II University of Naples, Naples, Italy
* Corresponding author; email: nikhil_munshi{at}dfci.harvard.edu.
The transformation from Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) is believed to be associated with changes in immune processes. We have therefore employed Serological analysis of Recombinant cDNA Expression Library (SEREX) to screen the sera of MGUS patients to identify Tumor-Associated Antigens (TAAs). A total of ten antigens were identified, with specific antibody responses in MGUS patients. Responses appeared to be directed against intracellular proteins involved in a variety of cellular functions, including apoptosis (SON, IFT57/HIPPI), DNA and RNA binding (ZNF292, GPATCH4), signal transduction regulators (AKAP11), transcriptional co-repressor (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) showed responses in 6/29 (20.6%) MGUS patients but 0/11 newly diagnosed MM patients. Interestingly, 3/11 (27.2%) MM patients following autologous stem-cell transplants showed responses to OFD1. We have confirmed T cell responses against OFD1 in MGUS and also observed down-regulation of Gli1/Ptch1 and p- -catenin following OFD1 knock-down with specific siRNA, suggesting its functional role in the regulation of Hh- and Wnt-pathway. These findings demonstrate OFD1 as an important immune target and highlight its possible role in signal transduction and tumorigenesis in MGUS and MM.
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