The G-CSFR has also been implicated in the etiology of disease, with mutations/variants of G-CSFR implicated in neutropenia, myelodysplasia and leukemia.
Thus, leukemic transformation with acquisition of CSF3R mutations and monosomy 7 is not restricted to classical congenital neutropenia with autosomal inheritance, but can also occur in other genotypes of inherited neutropenia.
Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.
In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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.
Defects in G-CSFR expression due to targeted disruption of the G-CSFR gene or the genes for the transcription factors C/EBPalpha and PU.1 result in decreases in hematopoietic progenitor cell numbers and neutropenia.