CTLA-4 genotype and relapse incidence in patients with acute myeloid leukemia in first complete remission after induction chemotherapy

Hematology Department, Institut Catalàd'Oncologia, Girona, L'Hospitalet and Badalona, Spain.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 03/2009; 23(3):486-91. DOI: 10.1038/leu.2008.339
Source: PubMed


The recently described single-nucleotide polymorphism CT60, located in the 3'-untranslated region of the CTLA4 (cytotoxic T-lymphocyte antigen 4 ) gene, has been associated with susceptibility to several autoimmune diseases and has also been shown to be involved in immune responses following allogeneic stem cell transplantation (SCT). However, the contribution of the CTLA4 genotype to the control of minimal residual disease in patients with acute myeloid leukemia (AML) has yet to be explored. We investigated the association between the CTLA4 CT60 A/G genotype and the incidence of leukemic relapse in 143 adult patients with AML in first complete remission after the same chemotherapy protocol (CETLAM LAM'03). The CT60 AA genotype was associated with a higher rate of leukemic relapse (56.4 vs 35.6%, P=0.004; hazard ratio (HR)=2.64, 95% confidence interval (CI)=1.36-5.14) and lower overall survival at 3 years (39.4 vs 68.4%, P=0.004; HR=2.80, 95% CI=1.39-5.64). This is the first study to report an association between polymorphisms at CTLA-4 and AML relapse.

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    • "In fact, higher levels of sCTLA-4 were observed in individuals with +49A/G and CT60A haplotype. Interestingly, although the data in this field of research remain controversial, it has been recently shown that the same SNPs in the CTLA-4 coding region are also associated with susceptibility to human cancer [36], such as cervical squamous cell carcinoma [37], colorectal cancer [38], hepatocellular carcinoma [39], gastric cancer [40] and acute myeloid leukemia [41]. These results suggest that expression of CTLA-4 would be associated with a decreased ability of the immune system to detect and eliminate tumor-associated antigens. "
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    ABSTRACT: CTLA-4 is a key factor in regulating and maintaining self tolerance, providing a negative signal to the T cell and thus limiting immune responses. Several polymorphisms within the CTLA-4 gene have been associated with an increased risk of developing autoimmune diseases and, very recently, with susceptibility to human cancer. Acute lymphoblastic leukemia is a clonal disorder of lymphoid progenitors representing the most frequent malignancy of childhood. Here, we show the presence at significantly elevated levels of a circulating soluble form of CTLA-4 in 70% of B-ALL pediatric patients with active disease, the positive correlation between the percentage of leukemic B lymphocytes and the amount of serum sCTLA-4, and the expression of sCTLA-4 transcript by B cells in patients. Finally, a correlation between CD1d expression (a negative prognostic marker) and the sCTLA-4 in B-ALL patients was observed. This suggests a possible role of this soluble molecule as a marker of progression or severity of the neoplastic disease.
    PLoS ONE 09/2012; 7(9):e44654. DOI:10.1371/journal.pone.0044654 · 3.23 Impact Factor
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    • "Future studies have to consider how vaccination strategies should be designed to include all patients and not only selected subsets. Other immunogenetic factors also need to be considered then, for example, genetic polymorphisms in the chemokine system [71] or in T cell regulatory molecules [110]. "
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