Advertisement

Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFNγ

Luigi J. Alvarado, Heather D. Huntsman, Hai Cheng, Danielle M. Townsley, Thomas Winkler, Xingmin Feng, Cynthia E. Dunbar, Neal S. Young and Andre Larochelle

Key points

  • Excess IFNγ perturbs TPO-induced signaling pathways in human HSPCs; eltrombopag enhances HSPC function by overcoming this inhibition.

  • Steric occlusion of the low-affinity binding site of TPO to c-MPL by TPO:IFNγ heteromers contributes to perturbation of TPO signaling.

Abstract

The pro-inflammatory cytokine interferon-γ (IFNγ) has been implicated in human hematopoietic stem and progenitor cell (HSPC) depletion in immune-mediated bone marrow failure (BMF) syndromes. We show that IFNγ specifically prevents full engagement of thrombopoietin (TPO), a primary positive regulator of HSPC survival, to its receptor (c-MPL) via steric occlusion of the low-affinity binding site, contributing to perturbation of TPO-induced signaling pathways and decreased survival of human HSPCs. Eltrombopag, a synthetic small molecule mimetic of TPO that interacts with c-MPL at a position distinct from the extracellular binding site of TPO, bypasses this inhibition, providing an explanation for its clinical activity in BMF despite already elevated endogenous TPO levels. Thus, IFNγ-mediated perturbation of TPO:c-MPL complex formation and the resulting inhibition of a critical pathway of growth factor cell signaling may represent a general mechanism by which IFNγ impairs function of human HPSCs. This understanding could have broad therapeutic implications for various disorders of chronic inflammation.

  • Submitted November 8, 2018.
  • Accepted February 12, 2019.