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: Anna Kreutzman, Taina Jaatinen, Dario Greco, Emmi Vakkila, Johan Richter, Marja Ekblom, Henrik Hjorth-Hansen, Leif Stenke, Teresa Melo, Ron Paquette, Ruth Seggewiss-Bernhardt, Agnés Guerci-Bresler, Alexis Talbot, Jean Michel Cayuela, Francois-Xavier Mahon, Kimmo Porkka, Jeff Lipton, Jukka Partanen, Philippe Rousselot, Satu Mustjoki
• Journal: Experimental hematology (Exp Hematol) Vol. 40 Issue 11 Pg. 906-913.e1 (Nov 2012) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 22842045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Pyrimidines
• Receptors, KIR
• Thiazoles
• Dasatinib

Topics

• Antineoplastic Agents (therapeutic use)
• Dasatinib
• Gene Expression Profiling
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics)
• Pyrimidines (therapeutic use)
• Receptors, KIR (genetics)
• Thiazoles (therapeutic use)