TY - JOUR
T1 - Tyrosinekinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling
AU - De Lavallade, Hugues
AU - Khoder, Ahmad
AU - Hart, Melanie
AU - Sarvaria, Anushruti
AU - Sekine, Takuya
AU - Alsuliman, Abdullah
AU - Mielke, Stephan
AU - Bazeos, Alexandra
AU - Stringaris, Kate
AU - Ali, Sara
AU - Milojkovic, Dragana
AU - Foroni, Letizia
AU - Chaidos, Aristeidis
AU - Cooper, Nichola
AU - Gabriel, Ian
AU - Apperley, Jane
AU - Belsey, Sarah
AU - Flanagan, Robert J.
AU - Goldman, John
AU - Shpall, Elizabeth J.
AU - Kelleher, Peter
AU - Marin, David
AU - Rezvani, Katayoun
PY - 2013
Y1 - 2013
N2 - Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
AB - Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
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U2 - 10.1182/blood-2012-11-465039
DO - 10.1182/blood-2012-11-465039
M3 - Article
C2 - 23719297
AN - SCOPUS:84884291198
SN - 0006-4971
VL - 122
SP - 227
EP - 238
JO - Blood
JF - Blood
IS - 2
ER -