Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients

S Thiant,M Guimond,D M Leboeuf,M M Moutuou,L Busque,R Sidi Boumedine,J Roy,P Laflamme

doi:10.1038/bcj.2017.29

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.

Highlights

Imatinib mesylate (IM) is currently the drug of choice for first line therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML)
T lymphocytes require T cell receptor (TCR) stimulation by MHC-I or MHC-II and IL-7 signaling in order to survive and persist in the periphery
While TCR signaling induces the phosphorylation and activation of AKT by the lipid kinase phosphatidylinositol 3-kinase (PI3K), IL-7 signaling induces the phosphorylation of STAT5 (STAT5p) by Jak[1,2,3] protein kinases; these pathways constitute potential targets for IM.[5,6]

Summary

INTRODUCTION

Imatinib mesylate (IM) is currently the drug of choice for first line therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML). While TCR signaling induces the phosphorylation and activation of AKT by the lipid kinase phosphatidylinositol 3-kinase (PI3K), IL-7 signaling induces the phosphorylation of STAT5 (STAT5p) by Jak[1,2,3] protein kinases; these pathways constitute potential targets for IM.[5,6] Despite ample evidence that IM can inhibit TCR signaling in vitro, the precise mechanism of action of IM on T cell homeostasis has remained inconclusive in vivo. The present studies were undertaken to precise the impact of IM on TCR or IL-7 inhibition in order to explain T cell lymphopenia in CML patients

MATERIALS AND METHODS

Findings

CONFLICT OF INTEREST