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Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in
Anna Kreutzman1, Taina Jaatinen, Dario Greco
1Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Abstract:
Tyrosine kinase inhibitors have greatly improved the prognosis of chronic myeloid leukemia (CML). In addition to direct kinase inhibition, their effects can also be mediated through immune modulation, such as expansion of cytotoxic T and natural-killer cells observed during dasatinib therapy. As natural-killer cell and partially CD8(+) T-cell function are regulated by killer immunoglobulin-like receptors (KIRs), we studied whether the KIR gene profile is associated with clinical therapy response in dasatinib-treated CML patients (n = 191). In first-line patients, the absence of the inhibitory KIR2DL5A (p = 0.0489), 2DL5B (p = 0.030), and 2DL5all (p = 0.0272) genes were associated with improved molecular response at the 12-month time point. In addition, the same trend was seen with two activating KIR genes, 2DS1 (p = 0.061) and 2DS2 (p = 0.071). Furthermore, when patients were clustered into two groups by their KIR gene profile, the BCR-ABL1 transcript levels differed significantly between the groups (p = 0.047), showing that patients who lacked several KIR genes had better response. The comparison of first-line and second-line patients did not show any significant differences in either KIR or human leukocyte antigen genotypes. Our results show that immunogenetic factors, such as the KIR gene profile, can play a role in tyrosine kinase inhibitor therapy response. Additional studies are warranted to elucidate the functional significance of KIR genes associated with treatment outcomes.
Insights
Killer immunoglobulin-like receptor (KIR) gene profiles are linked to better outcomes in chronic myeloid leukemia (CML) patients treated with dasatinib. Patients lacking specific inhibitory KIR genes showed improved molecular response, suggesting immunogenetics influences CML treatment effectiveness.
Area of Science:
- Immunogenetics
- Hematology
- Oncology
Background:
- Tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukemia (CML) treatment.
- TKIs like dasatinib can modulate immune responses, including natural killer (NK) cell activity.
- Natural killer cell function is regulated by killer immunoglobulin-like receptors (KIRs).
Purpose of the Study:
- To investigate the association between killer immunoglobulin-like receptor (KIR) gene profiles and clinical therapy response in dasatinib-treated CML patients.
- To determine if specific KIR genotypes correlate with treatment outcomes in CML.
Main Methods:
- Genotyping of KIR genes in 191 CML patients receiving dasatinib therapy.
- Analysis of the association between KIR gene profiles and molecular response at 12 months.
- Comparison of KIR and HLA genotypes between first-line and second-line treatment groups.
Main Results:
- Absence of inhibitory KIR2DL5A, KIR2DL5B, and KIR2DL5all genes was associated with improved molecular response at 12 months in first-line CML patients.
- A trend towards improved response was observed with activating KIR2DS1 and KIR2DS2 genes.
- Patients lacking several KIR genes exhibited significantly lower BCR-ABL1 transcript levels, indicating a better treatment response.
Conclusions:
- KIR gene profiles represent a potential immunogenetic factor influencing dasatinib therapy response in CML.
- The findings suggest that KIR genotypes may predict treatment outcomes in CML patients.
- Further research is needed to understand the functional role of KIR genes in TKI therapy response.
