| RRC ID |
67314
|
| 著者 |
Ureshino H, Shindo T, Kojima H, Kusunoki Y, Miyazaki Y, Tanaka H, Saji H, Kawaguchi A, Kimura S.
|
| タイトル |
Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML.
|
| ジャーナル |
Cancer Immunol Res
|
| 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.
|
| 巻・号 |
6(6)
|
| ページ |
745-754
|
| 公開日 |
2018-6-1
|
| DOI |
10.1158/2326-6066.CIR-17-0462
|
| PII |
2326-6066.CIR-17-0462
|
| PMID |
29695383
|
| MeSH |
Adult
Aged
Aged, 80 and over
Alleles*
Biomarkers
Biomarkers, Tumor
Female
HLA Antigens / genetics*
HLA Antigens / immunology
Haplotypes
Humans
Immunophenotyping
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality*
Male
Middle Aged
Pharmacogenomic Variants*
Polymorphism, Genetic*
Prognosis
Protein-Tyrosine Kinases / pharmacology
Protein-Tyrosine Kinases / therapeutic use
Receptors, KIR / genetics*
Treatment Outcome
Young Adult
|
| IF |
8.728
|
| リソース情報 |
| ヒト・動物細胞 |
K562(RCB0027) |
