THE PROTEIN-TYROSINE KINASE JAK2 IS ACTIVATED IN NEUTROPHILS FROM PATIENTS WITH SEVERE CONGENITAL NEUTROPENIA

Severe congenital neutropenia (SCN; or Kostmann syndrome) is an autoso mal recessive disorder characterized by a maturation arrest of myelopo iesis at the level of promyelocytes. Myeloid precursor cells from pati ents with SCN require pharmacological dosages of recombinant human gra nulocyte colony-stimulating factor (r-metHuG-CSF; Filgrastim; Amgen, T housand Oaks, CA) to differentiate to normal neutrophils. Thus, it is hypothesized that the underlying defect responsible for SCN is based o n an abnormal G-CSF-induced signal transduction pathway, Because JAK2, a nonreceptor tyrosine kinase, is involved in the signaling pathway o f G-CSF, we examined the expression and activity of JAK2 in neutrophil s from SCN patients during r-metHuG-CSF treatment. The immunoprecipita ted JAK2 protein showed increased tyrosine phosphorylation in neutroph ils from SCN patients as compared with that in neutrophils from health y donors, suggesting that this kinase is activated. In vitro kinase as says of immunoprecipitated JAK2 confirmed that neutrophils from SCN pa tients show an increased autophosphorylation of JAK2 in comparison wit h that of neutrophils from healthy volunteers. These findings suggest that JAK2 is activated in SCN patients. (C) 1995 by The American Socie ty of Hematology,