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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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LYMPHOID NEOPLASIA

Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance

Simona Blotta13, Pierfrancesco Tassone3, Rao H. Prabhala1,2, Piersandro Tagliaferri3, David Cervi1, Samir Amin1,2, Jana Jakubikova1, Yu-Tzu Tai1, Klaus Podar1, Constantine S. Mitsiades1, Alessandro Zullo4, Brunella Franco4,5, Kenneth C. Anderson1, and Nikhil C. Munshi1,2

1 Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, MA; 2 Veterans Administration Boston Healthcare System, Harvard Medical School, Boston, MA; 3 University of Magna Græcia and Cancer Center, Catanzaro, Italy; 4 Telethon Institute of Genetics and Medicine, Naples, Italy; and 5 Medical Genetics Department of Pediatrics, Federico II University of Naples, Naples, Italy

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-β-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.


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