The role of interferon-gamma and its signaling pathway in pediatric hematological disorders

Pediatr Blood Cancer. 2021 Apr;68(4):e28900. doi: 10.1002/pbc.28900. Epub 2021 Jan 23.

Abstract

Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.

Keywords: HLH; aplastic anemia; graft failure; hematologic disorders; interferon-gamma; pediatric.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Benzoates / therapeutic use
  • Child
  • Drug Discovery
  • Hematologic Neoplasms / drug therapy
  • Hematologic Neoplasms / immunology
  • Hematologic Neoplasms / metabolism*
  • Hematologic Neoplasms / therapy*
  • Hematopoiesis / drug effects
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Hydrazines / therapeutic use
  • Immunotherapy
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Janus Kinases / antagonists & inhibitors
  • Nitriles
  • Pyrazoles / therapeutic use
  • Pyrimidines
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Benzoates
  • Hydrazines
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Interferon-gamma
  • ruxolitinib
  • Janus Kinases
  • eltrombopag