title: Evidence for BCR-ABL-dependent dysfunctions of iNKT cells from chronic myeloid leukemia patients.
abstract: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem-cell malignancy characterized by the presence of the chimeric BCR-ABL oncoprotein with deregulated tyrosine-kinase (TK) activity. Although conventional T cells are acknowledged as important players in the control of CML, a possible modification of invariant NKT (iNKT) cells, known for their antitumoral activity, has not been established as yet. Here, we showed that the expression of perforin, CD95L, and promyelocytic leukemia zinc finger, a transcription factor required for maintenance of iNKT cell functions, was reduced or suppressed in CML patients at diagnosis, as compared with healthy individuals. The proliferation rate of blood iNKT cells in response to their cognate ligand was likewise diminished. These functional deficiencies were corrected in patients having achieved complete cytogenetic remission following TK inhibitor or IFN-α therapy. iNKT cells from CML patients in the chronic phase did not display increased TK activity, which argued against a direct autonomous action of BCR-ABL. Instead, we found that their anergic status originated from both intrinsic and APC-dependent dysfunctions. Our data demonstrate that chronic phase CML is associated with functional deficiencies of iNKT cells that are restored upon remission. These results suggest a possible contribution to disease control by TK inhibitor therapies.
authors.affiliation: INSERM UMR S935, Poitiers and Villejuif, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Rossignol
authors.forename: Anaïs
authors.initials: A
authors.lastname: Levescot
authors.forename: Florence
authors.initials: F
authors.lastname: Jacomet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Robin
authors.forename: Sara
authors.initials: S
authors.lastname: Basbous
authors.forename: Christine
authors.initials: C
authors.lastname: Giraud
authors.forename: Lydia
authors.initials: L
authors.lastname: Roy
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
authors.forename: Anne
authors.initials: A
authors.lastname: Barra
authors.forename: André
authors.initials: A
authors.lastname: Herbelin
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gombert
mesh_terms: D001549:Benzamides; D053222:Fas Ligand Protein / Q000097:blood; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000097:blood; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000201:enzymology / Q000276:immunology*; D054353:Perforin / Q000097:blood; D010879:Piperazines / Q000494:pharmacology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D001549:Benzamides; D053222:Fas Ligand Protein; D016898:Interferon-alpha; D051741:Kruppel-Like Transcription Factors; D010879:Piperazines; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D054353:Perforin; C092037:ZBTB16 protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases