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1.  Cancer-testis antigens: the current status on antigen regulation and potential clinical use 
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.
PMCID: PMC3301432  PMID: 22432085
Cancer-testis antigens; hematological malignancies; DNA methylation; heterogeneity of antigen expression
2.  Zap-70 positive chronic lymphocytic leukemia co-existing with Jak 2 V671F positive essential thrombocythemia: A common defective stem cell? 
Leukemia research  2008;33(6):854-855.
Essential thrombocythemia (ET) co-existing with chronic lymphocytic leukemia (CLL) is extremely rare. We report two cases of ET with Jak 2 V617F in Zap-70+ CLL. ET is a myeloproliferative stem cell disease. Zap-70 expression in CLL correlates with non-mutated immunoglobulin genes. The occurrence of a less mature CLL in patients with a pluripotential stem cell disease raises the possibility that an initial “trigger hit” occurred in a pre-Jak 2 common early progenitor in these patients. Subsequent additional molecular events accumulated independently following myeloid and lymphoid differentiation, leading to the development of two diseases of likely identical origin but different lineages.
doi:10.1016/j.leukres.2008.09.002
PMCID: PMC2695994  PMID: 18849073
ET; CLL; Zap-70; Jak 2 mutation
3.  Early renal arterial stent thrombosis associated with the JAK2 V617F mutation 
Leukemia research  2008;33(4):573-574.
doi:10.1016/j.leukres.2008.06.016
PMCID: PMC2695997  PMID: 18639337
4.  Core promoter sequence of SEMG I spans between the two putative GATA-1 binding domains and is responsive to IL-4 and IL-6 in myeloma cells 
Leukemia research  2008;33(1):166-169.
Semenogelin (SEMG) I is a Cancer-Testis antigen expressed in myeloma cells. SEMG I expression is upregulated by IL-4, IL-6 and 5-azacytidine. In this study, we set out to define the core promoter sequence needed for the expression of SEMG I in myeloma cells. We found that nucleotide sequences spanning the two putative GATA-1 binding domains are vital for the primary regulation of SEMG I promoter function while the other parts of the promoter sequence are responsible for the fine adjustment of the core promoter function. The core promoter sequence is responsive to the enhancing effect of IL-4 and IL-6.
doi:10.1016/j.leukres.2008.05.021
PMCID: PMC2605945  PMID: 18602691
Semenogelin I; Myeloma; GATA-1 binding domains; IL-4; IL-6
5.  Semenogelin I expression in myeloma cells can be upregulated pharmacologically 
Leukemia research  2008;32(12):1889-1894.
Semenogelin (SEMG) I is a Cancer-Testis (CT) antigen that we have found to be expressed in myeloma cells. In this study, we set out to determine whether the expression of SEMG I could be upregulated pharmacologically. We found that SEMG I expression in myeloma cells can be upregulated by 5-azacytidine, IL-4 and IL-6. The mechanisms of SEMG I gene upregulation by 5-azacytidine is unclear since there was no correlation between the methylation of the single CpG dinucleotide at position -11 and SEMG I expression. Both IL-4 and IL-6 appeared to enhance SEMG I expression through increasing its promoter function.
doi:10.1016/j.leukres.2008.03.036
PMCID: PMC2615790  PMID: 18468680
Semenogelin I; CT antigen; 5-azacytidine; IL-4; IL-6
6.  A panel of cancer-testis genes exhibiting broad-spectrum expression in haematological malignancies 
Cancer-testis (CT) antigens/genes show restricted expression in normal tissues but widespread expression in many tumour types. This, coupled with their ability to induce cytotoxic T-lymphocyte responses, makes them attractive vaccine candidates. Following our identification of PASD1, we have used RT-PCR to analyse the mRNA expression profile of a large panel of CT genes in cell lines derived from haematological malignancies, and have studied Sp17 protein expression in the same cell lines and diffuse large B-cell lymphoma (DLBCL) biopsies. Our extensive analysis revealed multiple CT transcripts exhibiting widespread expression across cell lines derived from 21 B- and 4 T-cell malignancies. The broadest mRNA expression profiles were observed for the following eight CT genes: Sp17 (25/25), PRAME (25/25), CSAGE (24/25), PASD1 (22/25), CAGE/DDX53 (19/25), CTAGE1 (19/25), HAGE/DDX43 (16/25) and PLU-1/JARID1B (15/25). Cell lines derived from more aggressive lymphoma subtypes generally expressed CT transcripts at higher frequency. Sp17 protein was detected in a number of cell lines and in six of eleven (54.5%) DLBCL biopsies. Analysis of Sp17 protein expression, by immunohistochemistry and Western blotting, broadens the scope of this CT antigen as a potentially relevant clinical target in haematological malignancies. Further studies of protein expression are now needed to validate these antigens as vaccine candidates.
PMCID: PMC2964014  PMID: 20726502
human; haematological cancer; CT antigens; RT-PCR; immunohistochemistry; Western blotting
7.  Identification of Protamine 1 as a novel CT antigen in early CLL 
British journal of haematology  2008;144(5):660-666.
Summary
Early chronic lymphocytic leukemia (CLL) is an ideal disease for immunotherapy. We previously showed that SEMG 1 is a Cancer-Testis (CT) antigen in CLL. In this study, we applied SEMG 1 as the bait in a yeast two-hybrid system of a testicular cDNA library. We isolated seven clones and identified Protamine (Prm) 1 as a novel CT antigen in early CLL. Prm 1 transcripts were detected in 11/41 (26.8%) patients. Prm 1 protein was also expressed but heterogeneously within individual patients. Of the 11 patients expressing Prm 1, four expressed Zap 70 protein and seven did not. These results, therefore, indicate that Prm 1 could potentially be a suitable target for the design of tumor vaccine for patients with early CLL, including for those with poor risk CLL. High titers Prm 1 IgG antibodies could be detected in 20 of these 41 CLL patients but not in any of the 20 healthy donors (p = 0.0001), suggesting the presence of Prm 1-reactive immune responses within immune repertoire of patients with early CLL. Further work is warranted, especially in approaches to upregulate Prm 1 expression, to determine the role of Prm 1 as an immunotherapeutic target for early CLL.
doi:10.1111/j.1365-2141.2008.07502.x
PMCID: PMC2752686  PMID: 19036087
Protamine 1; CT antigen; CLL; Zap 70

Results 1-7 (7)