BACKGROUND: Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes. DESIGN AND METHODS: We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population. RESULTS: We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls. CONCLUSIONS: In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
BACKGROUND: Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes. DESIGN AND METHODS: We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population. RESULTS: We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls. CONCLUSIONS: In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
Authors: C Bottino; S Sivori; M Vitale; C Cantoni; M Falco; D Pende; L Morelli; R Augugliaro; G Semenzato; R Biassoni; L Moretta; A Moretta Journal: Eur J Immunol Date: 1996-08 Impact factor: 5.532
Authors: N M Valiante; M Uhrberg; H G Shilling; K Lienert-Weidenbach; K L Arnett; A D'Andrea; J H Phillips; L L Lanier; P Parham Journal: Immunity Date: 1997-12 Impact factor: 31.745
Authors: B Quesnel; G Guillerm; R Vereecque; E Wattel; C Preudhomme; F Bauters; M Vanrumbeke; P Fenaux Journal: Blood Date: 1998-04-15 Impact factor: 22.113
Authors: Qian Zhang; Hong Y Wang; Michal Marzec; Puthiyaveettil N Raghunath; Tomohiko Nagasawa; Mariusz A Wasik Journal: Proc Natl Acad Sci U S A Date: 2005-05-03 Impact factor: 11.205
Authors: J J M van Dongen; L Lhermitte; S Böttcher; J Almeida; V H J van der Velden; J Flores-Montero; A Rawstron; V Asnafi; Q Lécrevisse; P Lucio; E Mejstrikova; T Szczepański; T Kalina; R de Tute; M Brüggemann; L Sedek; M Cullen; A W Langerak; A Mendonça; E Macintyre; M Martin-Ayuso; O Hrusak; M B Vidriales; A Orfao Journal: Leukemia Date: 2012-05-03 Impact factor: 11.528
Authors: E Poullot; R Zambello; F Leblanc; B Bareau; E De March; M Roussel; M L Boulland; R Houot; A Renault; T Fest; G Semenzato; T Loughran; T Lamy Journal: Ann Oncol Date: 2014-08-05 Impact factor: 32.976