Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies

Harrington Cancer Center, Amarillo, Texas, United States
Blood (Impact Factor: 10.45). 03/2003; 101(3):955-60. DOI: 10.1182/blood-2002-06-1930
Source: PubMed


Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation between SPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.

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Available from: Maurizio Chiriva-Internati, Mar 18, 2014
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    • "ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 158, 700–711 research paper broad range of cellular and humoral immune responses. In myeloma, several reports have described sporadic overexpression of CTA and accompanying CTA-specific T cell and B cell responses (Lim et al, 2001; Wang et al, 2003; Jungbluth et al, 2005; Van Rhee et al, 2005; Condomines et al, 2007). Induced CTA alloreactivity has also been reported in MM patients undergoing allografting, possibly associated with freedom from relapse (Atanackovic et al, 2007). "
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    ABSTRACT: Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.
    British Journal of Haematology 07/2012; 158(6):700-11. DOI:10.1111/j.1365-2141.2012.09225.x · 4.71 Impact Factor
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    • "MM (82%) [17] NY-ESO-1 Xq28 MM (60%) [18] SLLP 1 17q11.2 AML (22%); CML (29%); CLL (29%); MM (35%) [19] SPAN-Xb Xq27.1 MM (20%); CML (60%); CLL (33%); AML (50%) [20] SCP1 1p13-p12 MM (10%); CML (23%); AML (5.7%) [21] SEMG 1 20q12-q13.2 CML (62%); CLL (42%); CLL (42%); MM (7%) [22] "
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    ABSTRACT: Immunotherapy is theoretically an attractive therapeutic option for patients with hematological malignancies. Various laboratory studies suggested the importance of the choice of tumor antigen for successful immunotherapy. Cancer-testis antigens (CTAs) are potentially suitable molecules for tumor vaccines of hematological malignancies because of their high immunogenicity in vivo, even in cancer-bearing patients, and their relatively restricted normal tissue distribution. Tumor cell kill using a CTA-based immunotherapy will, therefore, be more specific and associated with less toxicities when compared to chemotherapy. Many CTAs have been identified in various hematologic malignancies. In this review, we will take the readers through the journey of hopes and the disappointments arisen from the discovery of CTAs. We will describe the features of CTAs and their expression in hematologic malignancies. We will also discuss the mechanisms regulating the expression of these CTAs, from a primary regulatory mechanism involving DNA methylation to secondary controls by cytokines. Finally, we will address the potential obstacles that will prevent the successful use of CTAs as targets for tumor immunotherapy.
    American Journal of Blood Research 01/2012; 2(1):29-35.
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    • "SPANX proteins are normally expressed in germ cells;4,10 however, their expression has also been detected in a number of tumors, including melanoma, myeloma, glyoblastoma, breast carcinoma, prostate cancer, and testicular germ cell tumors.5,11–14 The present study was undertaken to evaluate the expression of SPANX proteins in normal prostate tissues and in prostate cancer by immunohistochemistry. "
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    ABSTRACT: The sperm protein associated with the nucleus in the X chromosome (SPANX) gene family encode for proteins that are not only expressed in germ cells, but also in a number of tumors. In addition, SPANX genes map in an interval of the X chromosome (namely, Xq27), which has been found to be associated with familial prostate cancer by linkage analysis. The aim of this study was therefore to evaluate SPANX protein expression in normal prostate tissues and in prostate carcinoma. For this purpose, formalin-fixed and paraffin-embedded sections obtained from 15 normal (at autopsy) donors and 12 men with prostate cancer were analyzed by immunohistochemistry. About 40% of both normal and tumor prostate samples resulted SPANX positive. Signals were exclusively with the nucleus in normal prostate cells, whereas both nuclear and cytoplasmic positivity was observed in tumor cells. In conclusion, these findings showed that SPANX genes are expressed in both normal and tumor prostate gland, but the latter showed a peculiar cytoplasmic staining positivity. This suggests a possible association between SPANX over expression and prostate cancer development. Additional studies are needed to corroborate this hypothesis.
    European journal of histochemistry: EJH 09/2010; 54(3):e41. DOI:10.4081/ejh.2010.e41 · 2.04 Impact Factor
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