Abstract
In a proportion of patients with chronic myeloid leukemia (CML) being treated with dasatinib, we recently observed large granular lymphocyte (LGL) expansions carrying clonal T-cell receptor (TCR) gamma/delta gene rearrangements. To assess the prevalence and role of clonal lymphocytes in CML, we collected samples from patients (n = 34) at the time of diagnosis and during imatinib and dasatinib therapies and analyzed lymphocyte clonality with a sensitive polymerase chain reaction-based method of TCR gamma and delta genes. Surprisingly, at CML diagnosis, 15 of 18 patients (83%) had a sizeable clonal, BCR-ABL1 negative lymphocyte population, which was uncommon in healthy persons (1 of 12; 8%). The same clone persisted at low levels in most imatinib-treated patients. In contrast, in a distinct population of dasatinib-treated patients, the diagnostic phase clone markedly expanded, resulting in absolute lymphocytosis in blood. Most patients with LGL expansions (90%) had TCR delta rearrangements, which were uncommon in patients without an LGL expansion (10%). The TCR delta clones were confined to gammadelta(+) T- or natural killer-cell compartments and the TCR gamma clones to CD4(+)/CD8(+) alphabeta(+) fractions. The functional importance of clonal lymphocytes as a part of leukemia immune surveillance and the putative anergy-reversing role of dasatinib require further evaluation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Antineoplastic Agents / therapeutic use*
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Benzamides
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CD8-Positive T-Lymphocytes / chemistry
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CD8-Positive T-Lymphocytes / pathology
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Clonal Anergy
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Clone Cells / chemistry
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Clone Cells / pathology*
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Cytomegalovirus / physiology
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Dasatinib
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Female
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Fusion Proteins, bcr-abl / analysis
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
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Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
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Humans
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Imatinib Mesylate
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Immunologic Surveillance
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Killer Cells, Natural / chemistry
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Killer Cells, Natural / pathology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / virology
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Lymphocyte Count
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Male
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Middle Aged
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Piperazines / therapeutic use
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / therapeutic use*
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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T-Lymphocyte Subsets / chemistry
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T-Lymphocyte Subsets / pathology*
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Thiazoles / therapeutic use*
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Virus Activation / drug effects
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Young Adult
Substances
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Antineoplastic Agents
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Benzamides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Receptors, Antigen, T-Cell, gamma-delta
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Thiazoles
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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Dasatinib