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Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia

Kreutzman, Anna; Jaatinen, Taina; Greco, Dario; Vakkila, Emmi; Richter, Johan LU ; Ekblom, Marja LU ; Hjorth-Hansen, Henrik; Stenke, Leif; Melo, Teresa and Paquette, Ron, et al. (2012) In Experimental Hematology 40(11). p.906-913
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.... (More)
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. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. (Less)
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Experimental Hematology
volume
40
issue
11
pages
906 - 913
publisher
Elsevier
external identifiers
  • wos:000310182400005
  • scopus:84867399697
ISSN
1873-2399
DOI
10.1016/j.exphem.2012.07.007
language
English
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yes
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7a4b623e-f625-4da6-8a59-ef2bd87f9876 (old id 3284165)
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2013-01-07 09:43:17
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2017-11-05 03:09:06
@article{7a4b623e-f625-4da6-8a59-ef2bd87f9876,
  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. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.},
  author       = {Kreutzman, Anna and Jaatinen, Taina and Greco, Dario and Vakkila, Emmi and Richter, Johan and Ekblom, Marja and Hjorth-Hansen, Henrik and Stenke, Leif and Melo, Teresa and Paquette, Ron and Seggewiss-Bernhardt, Ruth and Guerci-Bresler, Agnes and Talbot, Alexis and Cayuela, Jean Michel and Mahon, Francois-Xavier and Porkka, Kimmo and Lipton, Jeff and Partanen, Jukka and Rousselot, Philippe and Mustjoki, Satu},
  issn         = {1873-2399},
  language     = {eng},
  number       = {11},
  pages        = {906--913},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia},
  url          = {http://dx.doi.org/10.1016/j.exphem.2012.07.007},
  volume       = {40},
  year         = {2012},
}