Analysis of killer cell immunoglobulin-like receptor genotypes in acute and chronic myeloid leukemia
Abstract
Purpose: Interactions between natural killer (NK)-expressed killer-cell immunoglobulin-like receptors (KIRs) and Major Histocompatibility Complex (MHC) class I molecules determine immune responses against tumour cells. Previous studies have shown that alloreactive potential of NK cells provide a promising treatment option for patients with hematological malignancies. The aim of this study was to investigate the KIR genes and genotypes in patients with acute myeloid leukemia (AML) and chronic myeloid leukemias (CML).
Materials and Methods: We investigated the frequency of KIR in AML (n=34) and CML (n=56) patients from Southern (Mediterranean) region of Türkiye and compared the results with 100 healthy controls. Polymerase chain reaction (PCR) and sequence-specific oligonucleotide (SSO) methods were used to identify KIR genes in peripheral blood samples.
Results: We observed an increased frequency of inhibitory KIR2DL3 in myeloid leukemia patients (91.3%) compared to controls (78%). Additionally, the frequency of KIR2DL3 was significantly higher in CML patients compared to controls (93.5% vs. 78%,). Notably, there was also a decreased incidence of inhibitory KIR2DL2 and its activating counterpart KIR2DS2 in CML patients compared to controls (34.8% vs. 52%, both, respectively). Additionally, there was a tendency for inhibitory KIR genes to predominate in patients with myeloid leukemia.
Conclusion: Our findings suggest a potential role for the KIR genes in the pathogenesis of myeloid leukemia. Further studies are needed to investigate the relationships between KIR gene polymorphisms and human leukocyte antigen (HLA) ligands in leukemia and the impact of NK cell responses on clinical outcomes.
Ethical Statement
The study was approved by the institutional review board of Çukurova University.
Supporting Institution
Scientific Research Projects were supported by Çukurova University.
References
- Kulkarni S, Martin MP, Carrington M. The yin and yang of HLA and KIR in human disease. Semin Immunol. 2008;20:343-52.
- Agnello L, Masucci A, Tamburello M, Facciotti F, Santoni A, Moretta L et al. The role of killer Ig-like receptors in diseases from A to Z. Int J Mol Sci. 2025;26:3242.
- Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR). Cancer Biol Ther. 2009;8:2211-20.
- Zitvogel L, Apetoh L, Ghiringhelli F, Smyth MJ, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59-73.
- Lotzova E, Savary CA, Herberman RB. Inhibition of clonogenic growth of fresh leukemia cells by unstimulated and IL-2 stimulated NK cells of normal donors. Leuk Res. 1987;11:1059-66.
- Ruggeri L, Capanni M, Casucci M, Aversa F, Moretta L, Moretta A et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333-9.
- Middleton D, Diler AS, Meenagh A, Farrell L, Curran MD, Barnardo MC et al. Killer immunoglobulin-like receptors (KIR2DL2 and/or KIR2DS2) in presence of their ligand (HLA-C1 group) protect against chronic myeloid leukaemia. Tissue Antigens. 2009;73:553-60.
- Varbanova VP, Mihailova S, Naumova E, Pavlova E, Ivanova M, Kostova E et al. Certain killer immunoglobulin-like receptor (KIR)/KIR HLA class I ligand genotypes influence natural killer antitumor activity in myelogenous leukemia but not in acute lymphoblastic leukemia: a case control leukemia association study. Turk J Haematol. 2019;36:238-46.
- Ali S, Sergeant R, O'Brien SG, Goldman JM, Melo JV, Apperley JF et al. Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia. Blood. 2012;120:697-8.
- Marin D, Gabriel IH, Ahmad S, Mahmud N, Agrawal V, Rea D et al. KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib. Leukemia. 2012;26:296-302.
- Alavianmehr A, Mansouri M, Ramzi M, Ghavami S, Shirazi F, Farsinejad A et al. Association of killer-cell immunoglobulin-like receptor genes with acute myelogenous leukaemia. Int J Immunogenet. 2020;47:512-21.
- Heidenreich F, Falk B, Baldauf H, von Bonin M, Witzens-Harig M, Heuser M et al. Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia. Blood Adv. 2023;7:2994-3004.
- Middleton D, Menchaca L, Rood H, Komerofsky R, Mao M, Vierra-Green C et al. New allele frequency database: http://www.allelefrequencies.net. Tissue Antigens. 2003;61:403-7.
- Jiang M, Guo X, Yuan L, Xu Y, Han M, Zhang Z et al. Killer cell immunoglobulin-like receptor gene cluster predisposes to susceptibility to B-cell acute lymphoblastic leukemia in Chinese children. Int J Clin Exp Pathol. 2020;13:536-42.
- Dizaji Asl K, Rafat A, Mazloumi Z, Ghaderi A, Soleimani M, Dalirfardouei R et al. Cord blood stem cell-generated KIR(+)NK cells effectively target leukemia cell lines. Hum Immunol. 2023;84:98-105.
- Debska-Zielkowska J, Moszkowska G, Zielinski M, Baranska M, Bednarz-Knoll N, Tafil-Klawe M et al. KIR receptors as key regulators of NK cells activity in health and disease. Cells. 2021;10:1777.
- Makanga DR, Jullien M, David G, Damoiseaux J, Six A, Schleinitz N et al. Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response. Oncoimmunology. 2021;10:1936392..
- Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-100.
- Schellekens J, Gagne K, Marsh SG. Natural killer cells and killer-cell immunoglobulin-like receptor polymorphisms: their role in hematopoietic stem cell transplantation. Methods Mol Biol. 2014;1109:139-58.
- Misra MK, Prakash S, Moulik NR, Kumar S, Singh M, Agarwal S et al. Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians. Hum Immunol. 2016;77:41-6.
- Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201-14.
- La Nasa G, Caocci G, Littera R, Campus F, Usai P, Carcassi C et al. Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients. Exp Hematol. 2013;41:424-31.
- Varbanova V, Naumova E, Mihaylova A. Killer-cell immunoglobulin-like receptor genes and ligands and their role in hematologic malignancies. Cancer Immunol Immunother. 2016;65:427-40.
- Guethlein LA, Beyzaie N, Nemat-Gorgani N, Horowitz A, Trachtenberg EA, Parham P et al. Following transplantation for acute myelogenous leukemia, donor KIR Cen B02 better protects against relapse than KIR Cen B01. J Immunol. 2021;206:3064-72.
- Blunt MD, Vallejo Pulido A, Fisher JG, Peppa D, Frazier S, Costantini S et al. KIR2DS2 expression identifies NK cells with enhanced anticancer activity. J Immunol. 2022;209:379-90.
- Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18:2002-7.
- Zhang Y, Wang B, Ye S, Gao X, Tang K, Wang J et al. Killer cell immunoglobulin-like receptor gene polymorphisms in patients with leukemia: possible association with susceptibility to the disease. Leuk Res. 2010;34:55-8.
- Shahsavar F, Tajik N, Entezami KZ, Rezaei N, Khosravi A, Shokri F et al. KIR2DS3 is associated with protection against acute myeloid leukemia. Iran J Immunol. 2010;7:8-17.
- Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8-19.
- Ozturk OG, Polat G, Atik U. Diversity of killer cell immunoglobulin-like receptor genes in Southern Turkey. Mol Biol Rep. 2012;39:1989-95.
- Yeung DT, Tang C, Vidovic L, Ku E, Hiyama K, Kroger N et al. KIR2DL5B genotype predicts outcomes in CML patients treated with response-directed sequential imatinib/nilotinib strategy. Blood. 2015;126:2720-3.
- Kreutzman A, Jaatinen T, Greco D, Syrjälä K, Rajala H, Partanen J et al. Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia. Exp Hematol. 2012;40:906-13.e1.
Abstract
Amaç: Doğal öldürücü (NK) tarafından ifade edilen killer-cell immunoglobulin-like receptors (KIR'lar) ile major doku uygunluk kompleksi (MHC) sınıf I molekülleri arasındaki etkileşimler, tümör hücrelerine karşı bağışıklık tepkilerini belirler. Önceki çalışmalar, NK hücrelerinin alloreaktif potansiyelinin hematolojik maligniteli hastalar için umut verici bir tedavi seçeneği sunduğunu göstermiştir. Bu çalışmanın amacı akut miyeloid lösemi (AML) ve kronik miyeloid lösemi (KML) hastalarında KIRgenlerini ve genotiplerini araştırmaktır.
Gereç ve Yöntem: Türkiye'nin güney (Akdeniz) bölgesinde AML (n=34) ve KML (n=56) hastalarında KIR sıklığı araştırıldı ve bu sonuçlar 100 sağlıklı kontrolle karşılaştırıldı. Periferik kan örneklerinden KIR genlerini tanımlamak için polimeraz zincir reaksiyonu (PCR) ve dizi spesifik oligonükleotid (SSO) yöntemi kullanıldı.
Bulgular: Myeloid lösemi hastalarında (%91,3) kontrollerle (%78) karşılaştırıldığında inhibitör KIR2DL3'ün artmış sıklığını gözlemledik. Ayrıca KIR2DL3 sıklığı KML hastalarında kontrol grubuna göre anlamlı derecede yüksekti (%93,5'e karşı %78). Özellikle KML hastalarında kontrollerle karşılaştırıldığında inhibitör KIR2DL2 ve onun aktive edici karşılığı olan KIR2DS2'nin insidansında azalma da mevcuttu (sırasıyla %34,8'e karşı %52, her ikisi de). Ek olarak, myeloid lösemi hastalarında inhibitör KIR genlerinin baskın olma eğilimi mevcuttu.
Sonuç: Bulgularımız miyeloid lösemilerin patogenezinde KIR genlerinin potansiyel bir rolüolduğunu göstermektedir. Lösemilerde KIR gen polimorfizmleri ile insan lökosit antijeni (HLA) ligandları arasındaki ilişkileri ve NK hücre yanıtlarının klinik sonuçlar üzerindeki etkisini araştıran daha fazla çalışma yapılması gerekmektedir.
Keywords
References
- Kulkarni S, Martin MP, Carrington M. The yin and yang of HLA and KIR in human disease. Semin Immunol. 2008;20:343-52.
- Agnello L, Masucci A, Tamburello M, Facciotti F, Santoni A, Moretta L et al. The role of killer Ig-like receptors in diseases from A to Z. Int J Mol Sci. 2025;26:3242.
- Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR). Cancer Biol Ther. 2009;8:2211-20.
- Zitvogel L, Apetoh L, Ghiringhelli F, Smyth MJ, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59-73.
- Lotzova E, Savary CA, Herberman RB. Inhibition of clonogenic growth of fresh leukemia cells by unstimulated and IL-2 stimulated NK cells of normal donors. Leuk Res. 1987;11:1059-66.
- Ruggeri L, Capanni M, Casucci M, Aversa F, Moretta L, Moretta A et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333-9.
- Middleton D, Diler AS, Meenagh A, Farrell L, Curran MD, Barnardo MC et al. Killer immunoglobulin-like receptors (KIR2DL2 and/or KIR2DS2) in presence of their ligand (HLA-C1 group) protect against chronic myeloid leukaemia. Tissue Antigens. 2009;73:553-60.
- Varbanova VP, Mihailova S, Naumova E, Pavlova E, Ivanova M, Kostova E et al. Certain killer immunoglobulin-like receptor (KIR)/KIR HLA class I ligand genotypes influence natural killer antitumor activity in myelogenous leukemia but not in acute lymphoblastic leukemia: a case control leukemia association study. Turk J Haematol. 2019;36:238-46.
- Ali S, Sergeant R, O'Brien SG, Goldman JM, Melo JV, Apperley JF et al. Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia. Blood. 2012;120:697-8.
- Marin D, Gabriel IH, Ahmad S, Mahmud N, Agrawal V, Rea D et al. KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib. Leukemia. 2012;26:296-302.
- Alavianmehr A, Mansouri M, Ramzi M, Ghavami S, Shirazi F, Farsinejad A et al. Association of killer-cell immunoglobulin-like receptor genes with acute myelogenous leukaemia. Int J Immunogenet. 2020;47:512-21.
- Heidenreich F, Falk B, Baldauf H, von Bonin M, Witzens-Harig M, Heuser M et al. Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia. Blood Adv. 2023;7:2994-3004.
- Middleton D, Menchaca L, Rood H, Komerofsky R, Mao M, Vierra-Green C et al. New allele frequency database: http://www.allelefrequencies.net. Tissue Antigens. 2003;61:403-7.
- Jiang M, Guo X, Yuan L, Xu Y, Han M, Zhang Z et al. Killer cell immunoglobulin-like receptor gene cluster predisposes to susceptibility to B-cell acute lymphoblastic leukemia in Chinese children. Int J Clin Exp Pathol. 2020;13:536-42.
- Dizaji Asl K, Rafat A, Mazloumi Z, Ghaderi A, Soleimani M, Dalirfardouei R et al. Cord blood stem cell-generated KIR(+)NK cells effectively target leukemia cell lines. Hum Immunol. 2023;84:98-105.
- Debska-Zielkowska J, Moszkowska G, Zielinski M, Baranska M, Bednarz-Knoll N, Tafil-Klawe M et al. KIR receptors as key regulators of NK cells activity in health and disease. Cells. 2021;10:1777.
- Makanga DR, Jullien M, David G, Damoiseaux J, Six A, Schleinitz N et al. Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response. Oncoimmunology. 2021;10:1936392..
- Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-100.
- Schellekens J, Gagne K, Marsh SG. Natural killer cells and killer-cell immunoglobulin-like receptor polymorphisms: their role in hematopoietic stem cell transplantation. Methods Mol Biol. 2014;1109:139-58.
- Misra MK, Prakash S, Moulik NR, Kumar S, Singh M, Agarwal S et al. Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians. Hum Immunol. 2016;77:41-6.
- Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201-14.
- La Nasa G, Caocci G, Littera R, Campus F, Usai P, Carcassi C et al. Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients. Exp Hematol. 2013;41:424-31.
- Varbanova V, Naumova E, Mihaylova A. Killer-cell immunoglobulin-like receptor genes and ligands and their role in hematologic malignancies. Cancer Immunol Immunother. 2016;65:427-40.
- Guethlein LA, Beyzaie N, Nemat-Gorgani N, Horowitz A, Trachtenberg EA, Parham P et al. Following transplantation for acute myelogenous leukemia, donor KIR Cen B02 better protects against relapse than KIR Cen B01. J Immunol. 2021;206:3064-72.
- Blunt MD, Vallejo Pulido A, Fisher JG, Peppa D, Frazier S, Costantini S et al. KIR2DS2 expression identifies NK cells with enhanced anticancer activity. J Immunol. 2022;209:379-90.
- Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18:2002-7.
- Zhang Y, Wang B, Ye S, Gao X, Tang K, Wang J et al. Killer cell immunoglobulin-like receptor gene polymorphisms in patients with leukemia: possible association with susceptibility to the disease. Leuk Res. 2010;34:55-8.
- Shahsavar F, Tajik N, Entezami KZ, Rezaei N, Khosravi A, Shokri F et al. KIR2DS3 is associated with protection against acute myeloid leukemia. Iran J Immunol. 2010;7:8-17.
- Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8-19.
- Ozturk OG, Polat G, Atik U. Diversity of killer cell immunoglobulin-like receptor genes in Southern Turkey. Mol Biol Rep. 2012;39:1989-95.
- Yeung DT, Tang C, Vidovic L, Ku E, Hiyama K, Kroger N et al. KIR2DL5B genotype predicts outcomes in CML patients treated with response-directed sequential imatinib/nilotinib strategy. Blood. 2015;126:2720-3.
- Kreutzman A, Jaatinen T, Greco D, Syrjälä K, Rajala H, Partanen J et al. Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia. Exp Hematol. 2012;40:906-13.e1.
Details
| Primary Language | English |
|---|---|
| Subjects | Innate Immunity, Haematological Tumours |
| Journal Section | Research |
| Authors | |
| Publication Date | June 30, 2025 |
| Submission Date | January 16, 2025 |
| Acceptance Date | June 10, 2025 |
| Published in Issue | Year 2025 Volume: 50 Issue: 2 |
