SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 are dramatically increased at the protein level in neutrophils from patients with severe congenital neutropenia (Kostmann's syndrome).

Severe congenital neutropenia (SCN) or Kostmann's syndrome is characterized by a stop in differentiation of myeloid progenitor cells at the myelocytic or promyelocytic stage. The pathophysiology of SCN is still unclear. We previously showed that the tyrosine kinase JAK2 is phosphorylated and activated in neutrophils from patients with severe congential neutropenia. We investigated the role of tyrosine phosphatases in this disease. Expression of the SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2 was analyzed in myeloid cells from patients with SCN in comparison to healthy donors. We investigated tyrosine phosphatase expression in myeloid cells at the protein level by Western blot analysis using polyclonal antisera against SHP-1 and SHP-2. Whereas SHP-1 and SHP-2 were hardly detectable in neutrophils from healthy donors, neutrophils from patients with SCN revealed high amounts of these two proteins in Western blot analyses. Reverse transcriptase-polymerase chain reaction and Northern blot analyses demonstrated no dramatic differences of SHP-1 mRNA in neutrophils from congenital neutropenia patients as compared to healthy donors. SHP-2 mRNA was hardly detectable in the neutrophils from patients and in normal neutrophils. Increased expression of SHP protein correlated with elevated activity of both SHP-1 and SHP-2 in neutrophils of patients with SCN. Taken together, these data indicate differential regulation for SHP-1 and SHP-2 at the protein level in neutrophils from SCN patients in comparison to healthy donors. We suggest that overexpression of SHP-1 and SHP-2 protein in neutrophils and not in mononuclear cells from patients with SCN might be related to the disease, e.g., by defective dephosphorylation of proteins involved in intracellular signaling pathways.