Inhibition of the Sec61 translocon overcomes cytokine-induced glucocorticoid resistance in T-cell acute lymphoblastic leukaemia

Br J Haematol. 2022 Jul;198(1):137-141. doi: 10.1111/bjh.18181. Epub 2022 Apr 17.

Abstract

Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance.

Keywords: Sec61 inhibitor; T-cell acute lymphoblastic leukaemia; cytokine; glucocorticoids.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Glucocorticoids / pharmacology
  • Humans
  • Interleukin-7
  • Metabolism, Inborn Errors
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Receptors, Glucocorticoid / deficiency
  • SEC Translocation Channels* / metabolism
  • T-Lymphocytes / metabolism

Substances

  • Cytokines
  • Glucocorticoids
  • Interleukin-7
  • Receptors, Glucocorticoid
  • SEC Translocation Channels
  • Dexamethasone

Supplementary concepts

  • Glucocorticoid Receptor Deficiency