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Cancer Immunology Research
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Research Articles

Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML

Hiroshi Ureshino, Takero Shindo, Hiroto Kojima, Yasushi Kusunoki, Yuki Miyazaki, Hidenori Tanaka, Hiroh Saji, Atsushi Kawaguchi and Shinya Kimura
Hiroshi Ureshino
1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
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  • ORCID record for Hiroshi Ureshino
Takero Shindo
1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
2Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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  • For correspondence: takeros@kuhp.kyoto-u.ac.jp
Hiroto Kojima
3HLA Foundation Laboratory, Kyoto, Japan.
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Yasushi Kusunoki
3HLA Foundation Laboratory, Kyoto, Japan.
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Yuki Miyazaki
3HLA Foundation Laboratory, Kyoto, Japan.
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Hidenori Tanaka
3HLA Foundation Laboratory, Kyoto, Japan.
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Hiroh Saji
3HLA Foundation Laboratory, Kyoto, Japan.
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Atsushi Kawaguchi
4Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan.
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Shinya Kimura
1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
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DOI: 10.1158/2326-6066.CIR-17-0462 Published June 2018
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Abstract

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR–HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109–3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745–54. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received August 27, 2017.
  • Revision received January 27, 2018.
  • Accepted April 20, 2018.
  • Published first April 25, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Immunology Research: 6 (6)
June 2018
Volume 6, Issue 6
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Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML
Hiroshi Ureshino, Takero Shindo, Hiroto Kojima, Yasushi Kusunoki, Yuki Miyazaki, Hidenori Tanaka, Hiroh Saji, Atsushi Kawaguchi and Shinya Kimura
Cancer Immunol Res June 1 2018 (6) (6) 745-754; DOI: 10.1158/2326-6066.CIR-17-0462

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Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML
Hiroshi Ureshino, Takero Shindo, Hiroto Kojima, Yasushi Kusunoki, Yuki Miyazaki, Hidenori Tanaka, Hiroh Saji, Atsushi Kawaguchi and Shinya Kimura
Cancer Immunol Res June 1 2018 (6) (6) 745-754; DOI: 10.1158/2326-6066.CIR-17-0462
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