GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling

Ann Hematol. 2017 Mar;96(3):345-353. doi: 10.1007/s00277-016-2894-5. Epub 2016 Dec 14.

Abstract

Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/μL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor. Recently, we detected that G-CSF induces granulopoiesis in CN patients by hyperactivation of nicotinamide phosphoribosyl transferase (NAMPT)/Sirtuin 1 signaling in myeloid cells. Here, we demonstrated that, in contrast to G-CSF, GM-CSF failed to induce NAMPT-dependent granulopoiesis in CN patients. We further identified NAMPT signaling as an essential downstream effector of the GM-CSF pathway in myelopoiesis.

Keywords: G-CSF; GM-CSF; NAMPT; Severe congenital neutropenia.

MeSH terms

  • Cells, Cultured
  • Congenital Bone Marrow Failure Syndromes
  • Cytokines / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use*
  • Humans
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Neutropenia / congenital*
  • Neutropenia / drug therapy
  • Neutropenia / metabolism
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Treatment Outcome

Substances

  • Cytokines
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3