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Expansion of highly differentiated CD8(+) T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

Kreutzman, A.; Ladell, K.; Koechel, C.; Gostick, E.; Ekblom, Marja LU ; Stenke, L.; Melo, T.; Einsele, H.; Porkka, K. and Price, D. A., et al. (2011) In Leukemia 25(10). p.1587-1597
Abstract
The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib... (More)
The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(_)(-) CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon. Leukemia (2011) 25, 1587-1597; doi:10.1038/leu.2011.135; published online 7 June 2011 (Less)
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published
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keywords
CMV, dasatinib, LGL, NK-cells, T-cells
in
Leukemia
volume
25
issue
10
pages
1587 - 1597
publisher
Nature Publishing Group
external identifiers
  • wos:000296147300009
  • scopus:80054026109
ISSN
1476-5551
DOI
10.1038/leu.2011.135
language
English
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yes
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d7f4ab85-466e-48b9-9793-54f259c7a0c7 (old id 2208165)
date added to LUP
2011-11-30 09:14:32
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2017-11-19 03:49:21
@article{d7f4ab85-466e-48b9-9793-54f259c7a0c7,
  abstract     = {The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(_)(-) CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon. Leukemia (2011) 25, 1587-1597; doi:10.1038/leu.2011.135; published online 7 June 2011},
  author       = {Kreutzman, A. and Ladell, K. and Koechel, C. and Gostick, E. and Ekblom, Marja and Stenke, L. and Melo, T. and Einsele, H. and Porkka, K. and Price, D. A. and Mustjoki, S. and Seggewiss, R.},
  issn         = {1476-5551},
  keyword      = {CMV,dasatinib,LGL,NK-cells,T-cells},
  language     = {eng},
  number       = {10},
  pages        = {1587--1597},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Expansion of highly differentiated CD8(+) T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation},
  url          = {http://dx.doi.org/10.1038/leu.2011.135},
  volume       = {25},
  year         = {2011},
}