The Carboxyl Terminus of the Granulocyte Colony-Stimulating Factor Receptor, Truncated in Patients with Severe Congenital Neutropenia/Acute Myeloid Leukemia, is Required for SH2-Containing Phosphatase-1 Suppression of Stat Activation

Kathleen E. Sullivan

Purpose of the Study. Some patients with severe congenital neutropenia harbor mutations in the carboxyl terminus of the granulocyte colony-stimulating factor (G-CSF) receptor. It is this subgroup of patients with severe congenital neutropenia that is markedly predisposed to acute myeloid leukemia. This predisposition poses a significant hurdle to management. Patients with severe congenital neutropenia are typically treated with G-CSF. In this subgroup, G-CSF could drive leukemogenesis and is contraindicated. This study examines the mechanism underlying the predisposition to malignancy.

Methods. Cell lines transfected with both wild-type and mutant G-CSF receptor cDNAs and SHP-1 negative cell lines were used to examine the effect of the mutation on signaling function. Electrophoretic mobility shift assays, Western blots, and transient transfections using reporter constructs were performed.

Results. The mutant receptors are paradoxically associated with an increased proliferative response to G-CSF despite the differentiative block in neutrophil development. The G-CSF receptor contains no intrinsic signaling activity, but activates Src family kinases, STAT 3/5, MAP kinases, and PI3 kinase. SHP-1 acts as a negative regulator. The mutant receptors are unable to interact effectively with SHP-1. The consequences of this impaired negative regulation are prolonged responses in the STAT pathways but not other signaling pathways. The exaggerated responses in the STAT pathways would explain the survival advantage of these cells and their hyperproliferation.

Conclusion. Failure of the mutant G-CSF receptors to interact effectively with the negative regulator SHP-1 appears to underlie the predisposition to acute myeloid leukemia.

Reviewer’s Comments. This study represents an important advance in our understanding of the secondary malignancies occurring in patients with severe congenital neutropenia. It should allow improved risk stratification for patients and could ultimately lead to improved management.