title: Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia.
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.
authors: Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors: Anna
authors: A
authors: Kreutzman
authors: Taina
authors: T
authors: Jaatinen
authors: Dario
authors: D
authors: Greco
authors: Emmi
authors: E
authors: Vakkila
authors: Johan
authors: J
authors: Richter
authors: Marja
authors: M
authors: Ekblom
authors: Henrik
authors: H
authors: Hjorth-Hansen
authors: Leif
authors: L
authors: Stenke
authors: Teresa
authors: T
authors: Melo
authors: Ron
authors: R
authors: Paquette
authors: Ruth
authors: R
authors: Seggewiss-Bernhardt
authors: Agnés
authors: A
authors: Guerci-Bresler
authors: Alexis
authors: A
authors: Talbot
authors: Jean Michel
authors: JM
authors: Cayuela
authors: Francois-Xavier
authors: FX
authors: Mahon
authors: Kimmo
authors: K
authors: Porkka
authors: Jeff
authors: J
authors: Lipton
authors: Jukka
authors: J
authors: Partanen
authors: Philippe
authors: P
authors: Rousselot
authors: Satu
authors: S
authors: Mustjoki
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib; D020869:Gene Expression Profiling; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D054340:Receptors, KIR / Q000235:genetics*; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D054340:Receptors, KIR; D013844:Thiazoles; D000069439:Dasatinib