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Association of KIR2DS4 and Its Variant KIR1D with Leukemia

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Association of KIR2DS4 and Its Variant KIR1D with Leukemia Letters to the Editor 2129 Association of KIR2DS4 and its variant KIR1D with leukemia Leukemia (2008) 22, 2129–2130; doi:10.1038/leu.2008.108; comparison with healthy subjects. We included 90 adults published online 8 May 2008 with chronic myeloid leukemia (CML, n ¼ 31), acute myeloid leukemia ( n ¼ 38), and acute lymphoblastic leukemia (n ¼ 21) who were candidates for allogeneic hematopoietic stem cell Natural killer (NK) cells are postulated to take part in innate transplantation. KIR2DS4n001 and KIR1D alleles were detected immunosurveillance against leukemia, contributing to both the according to previously described methodology5 in patients as disease control and clearance.1 A systematic review regarding well as in their HLA-matched related (n ¼ 31) or unrelated the role of NK cell receptors and their ligands in leukemia has (n ¼ 59) donors, serving as controls. Such selection of control recently been published by Verheyden and Demanet.1 group let us avoid potential bias resulting from the association of The activity of NK cells depends on the balance of activating HLA genotype with leukemia. All patients and donors were and inhibitory signals that are transmitted through respective Caucasoids. Patients and sibling donors were of Polish origin, receptors, including killer immunoglobulin-like receptors (KIRs). while the majority of unrelated donors were either Polish or HLA class I molecules are ligands for inhibitory KIRs, whereas German. As previously reported, the distribution of KIR genes ligands for their activating counterparts have not been well among these two populations is very similar.6 defined. As well, the physiological role of activating KIRs The frequencies of various allele combinations in patients, remains obscure and appears particularly intriguing in view of donors and population controls are listed in Table 1. The intact high degree of diversity with regard to the activating KIR gene KIR2DS4n001 was present in 20% of leukemia patients content in humans. In general, two major groups of haplotypes compared to 33.3% among the donors (P ¼ 0.04). The difference may be distinguished: haplotypes A with KIR2DS4 as the only was particularly distinct in a cohort of CML (19.4 vs 45.2%, activating KIR and haplotypes B characterized by the presence P ¼ 0.03), while it was not significant in acute myeloid leukemia of at least one activating KIR other than KIR2DS4. Furthermore, and acute lymphoblastic leukemia. The physiological role of various alleles of KIR2DS4 have been described including intact KIR2DS4 remains unknown and few data are available KIR2DS4n001 encoding cell membrane-anchored receptor regarding ligands for this receptor. Katz et al.,7 demonstrated resembling other activating KIRs and KIR2DS4n003, n005 and interaction of KIR2DS4 with HLA class I molecules, which, n006 (KIR1D) partial deletion variants, encoding protein devoid however, was restricted to HLA-Cw4 and characterized by low of transmembrane region and possessing only one immuno- affinity. On the other hand, the same group showed that globulin-like domain.2 The proteins encoded by KIR1D variants KIR2DS4 may recognize non-HLA class I ligands on melanoma are functionally inactive and therefore, a number of individuals cell lines and on a primary melanoma.8 That interaction was homozygous for hapolotype A and KIR1D do not have any shown to be both specific and functional and led to the killing of activating KIR. the target cells. In view of those findings, it cannot be excluded As demonstrated by Verheyden et al.,3,4 the presence of that the activating signal mediated by KIR2DS4 may confer particular KIRs and their HLA ligands may mediate susceptibility susceptibility of other cancers to NK cell-mediated lysis through to both myeloid and lymphoid leukemias. The authors first not yet recognized ligands. Our results strongly support this demonstrated higher number of inhibitory KIRs in leukemia hypothesis and indicate that CML cells may be a target for patients compared to healthy controls.3 The subsequent study KIR2DS4. revealed that negative effect of some inhibitory KIRs depends on KIR1D defective variants of KIR2DS4 are widely distributed simultaneous presence of their HLA ligands.4 In contrast, no among Caucasian populations, but its biological function has association was found between the genotype of activating not been discovered so far.6 In our study, the frequency of receptors and the incidence of leukemia. It must be noted, KIR1D was similar for patients and controls. However, in a however, that the authors did not discriminate between the setting of CML, the presence of KIR1D in the absence of intact KIR2DS4 and KIR1D variants. KIR2DS4n001 was detected significantly more frequently in The goal of our study was to verify whether the frequency of patients compared to their donors (77.4 vs 51.6%, P ¼ 0.03). KIR2DS4 allelic variants differs in patients with leukemia in Once again, no significant associations were found for acute Table 1 Frequencies of KIR2DS4 and its variant KIR1D among patients with leukemia and their hematopoietic stem cell donors KIR All leukemias CML AML ALL N ¼ 90 N ¼ 31 N ¼ 38 N ¼ 21 PD P DPDPD 2DS4*001À/1D+ 65 (72.2) 54 (60) 24 (77.4)* 16 (51.6) 26 (68.4) 23 (60.5) 15 (71.4) 15 (71.4) 2DS4*001+/1D+ 10 (11.1) 18 (20) 1 (3.2) 6 (19.4) 7 (18.4) 7 (18.4) 2 (9.5) 5 (23.8) 2DS4*001+/1DÀ 8 (8.9) 12 (13.3) 5 (16.1) 8 (25.8) 1 (2.6) 3 (7.9) 2 (9.5) 1 (4.8) 2DS4*001À/1DÀ 7 (7.8) 6 (6.7) 1 (3.2) 1 (3.2) 4 (10.5) 5 (13.2) 2 (9.5) 0 2DS4*001+ 18 (20)* 30 (33.3) 6 (19.4)* 14 (45.2) 8 (21.1) 10 (26.3) 4 (19) 6 (28.6) 1D+ 75 (83.3) 72 (80) 25 (80.6) 22 (71) 33 (86.8) 30 (78.9) 17 (81) 20 (95.2) Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; KIR, killer immunoglobulin- like receptor. Results are presented as numbers (%). P indicates patients; D, donors. *Po0.05 for comparisons of patients with their HLA-matched hematopoietic stem cell donors (w2 test or Fisher’s exact test for small counts). Leukemia Letters to the Editor 2130 myeloid leukemia and acute lymphoblastic leukemia. The 3Department of Microbiology and Biotechnology, Institute of lack of transmembrane domain indicates that the product Chemistry and Environmental Sciences, Faculty of Natural of KIR1D is a soluble protein. If it binds HLA class I and Sciences, Jan Dlugosz Pedagogical University, Czestochowa, other potential ligands in a way like fully functional KIRs, Poland E-mail: [email protected] then it may play a regulatory role by masking ligands for their receptors. Our observation suggests that such inter- action may be of particular importance in the absence of References intact KIR2DS4 and may decrease the activity of NK cells against CML. 1 Verheyden S, Demanet C. NK cell receptors and their ligands in In summary, KIR2DS4 appears to play important role in the leukemia. Leukemia 2008; 22: 249–257. regulation of NK cell-mediated immunosurveillance against 2 Maxwell LD, Wallace A, Middleton D, Curran MD. A common CML. Further investigation is warranted to determine ligands KIR2DS4 deletion variant in the human that predicts a soluble KIR for this receptor and to verify its association with other molecule analogous to the KIR1D molecule observed in the rhesus n monkey. Tissue Antigens 2002; 60: 254–258. diseases. Discrimination between intact KIR2DS4 001 and 3 Verheyden S, Bernier M, Demanet C. Identification of natural killer defective KIR1D variants appears essential in epidemiological cell receptor phenotypes associated with leukemia. Leukemia 2004; studies. 18: 2002–2007. 4 Verheyden S, Demanet C. Susceptibility to myeloid and lymphoid leukemia is mediated by distinct inhibitory KIR-HLA ligand Acknowledgements interactions. Leukemia 2006; 20: 1437–1438. 5 Gomez-Lozano N, Vilches C. Genotyping of human killer-cell The study was supported by the Grant no. 2 PO5B 155 28 from immunoglobulin-like receptor genes by polymerase chain reaction with sequence-specific primers: an update. Tissue Antigens 2002; the Polish Ministry of Science and Higher Education. 59: 184–193. 1 2 1 1 6 Luszczek W, Majorczyk E, Nowak I, Pawlik A, Jasek M, Wisniewski S Giebel , I Nowak , J Wojnar , M Krawczyk-Kulis , A et al. Inhibitory and activatory KIR gene frequencies in the Polish J Holowiecki1, S Kyrcz-Krzemien1 and P Kusnierczyk2,3 1 population. Int J Immunogenet 2006; 33: 167–170. Department of Hematology and Bone Marrow 7 Katz G, Markel G, Mizrahi S, Arnon TI, Mandelboim O. Recognition Transplantation, Silesian Medical University, Katowice, of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Poland; 2 Ig-like receptor two-domain short tail number 4. J Immunol 2001; Department of Clinical Immunology, Laboratory of 166: 7260–7267. Immunogenetics, Ludwik Hirszfeld Institute of Immunology 8 Katz G, Gazit R, Arnon TI, Gonen-Gross T, Tarcic G, Markel G et al. and Experimental Therapy, Polish Academy of Sciences, MHC class I-independent recognition of NK-activating receptor Wroclaw, Poland and KIR2DS4. J Immunol 2004; 173: 1819–1825. Reply to: Association of KIR2DS4 and its variant KIR1D with leukemia Leukemia (2008) 22, 2130–2131; doi:10.1038/leu.2008.109; tion.5,6 Moreover, it has been noted that populations with published online 8 May 2008 high KIR1D frequency would have a lower incidence of AA phenotype, because KIR2DS4 is the only activating KIR on the 1 AA phenotype. Consequently, individuals who are homozygous The letter of Giebel et al. shows that the frequency of the deleted for haplotype A and KIR1D will not have any functional KIR2DS4 variant (KIR1D) in absence of the intact membrane- 6,7 n activating KIR gene.
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