title: Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy.
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.
authors.affiliation: Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kreutzman
authors.forename: Vesa
authors.initials: V
authors.lastname: Juvonen
authors.forename: Veli
authors.initials: V
authors.lastname: Kairisto
authors.forename: Marja
authors.initials: M
authors.lastname: Ekblom
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.forename: Ruth
authors.initials: R
authors.lastname: Seggewiss
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000473:pathology; D017635:Clonal Anergy; D002999:Clone Cells / Q000737:chemistry / Q000473:pathology*; D003587:Cytomegalovirus / Q000502:physiology; D000069439:Dasatinib; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000037:antagonists & inhibitors; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D006801:Humans; D000068877:Imatinib Mesylate; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000737:chemistry / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000473:pathology*; D013844:Thiazoles / Q000627:therapeutic use*; D014775:Virus Activation / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib