title: Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients.
abstract: Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4+counts in their blood, yet CD8+counts are normal or even increased in some. Following the initiation of IM treatment, CD4+counts were further diminished and CD8+T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Thiant
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Moutuou
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Laflamme
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Sidi Boumedine
authors.affiliation: Départment de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: D M
authors.initials: DM
authors.lastname: Leboeuf
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Busque
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Roy
authors.affiliation: Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.|Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Guimond
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000009:adverse effects; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate