Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.

Abstract

The role of mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) in the pathogenesis of severe congenital neutropenia (SCN) and the subsequent development of acute myeloid leukemia (AML) is controversial. Mice carrying a targeted mutation of their G-CSFR that reproduces the mutation found in a patient with SCN and AML have been generated. The mutant G-CSFR allele is expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation have normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis is normal. However, in response to G-CSF treatment, these mice demonstrate a significantly greater fold increase in the level of circulating neutrophils. This effect appears to be due to increased neutrophil production as the absolute number of G-CSF-responsive progenitors in the bone marrow and their proliferation in response to G-CSF is increased. Furthermore, the in vitro survival and G-CSF-dependent suppression of apoptosis of mutant neutrophils are normal. Despite this evidence for a hyperproliferative response to G-CSF, no cases of AML have been detected to date. These data demonstrate that the G-CSFR mutation found in patients with SCN is not sufficient to induce an SCN phenotype or AML in mice. ( J. Clin. Invest. 1998. 102:483-492.)

SOCS3 Is a Physiological Negative Regulator for Granulopoiesis and Granulocyte Colony-stimulating Factor Receptor Signaling

“…SOCS3 is reminiscent of the phenotype derived from the G-CSF receptor mutant found in human severe congenital neutropenia (32,33). The hypergranulopoiesis of mutant mice bearing this receptor correlated with the prolonged activation of STAT1, STAT3, and STAT5 in response to G-CSF treatment (34).…”

Novel role of WD40 and SOCS box protein-2 in steady-state distribution of granulocyte colony-stimulating factor receptor and G-CSF-controlled proliferation and differentiation signaling

“…These mutations are linked with progression of SCN to acute myeloid leukemia (AML) . The truncated G-CSF-Rs confer a hyperproliferative response to G-CSF in knockin mouse models and are unable to transduce differentiation signals in 32D cells (Dong et al, 1998;McLemore et al, 1998;Hermans et al, 1999;Ward et al, 1999b;Aarts et al, 2004). These mutants are defective in internalization, supporting the importance of a tight control of G-CSF-R membrane expression for a balanced signaling output (Hunter and Avalos, 1999;Ward et al, 1999b;Aarts et al, 2004).…”

An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia

“…12,13 Increased G-CSF responsiveness and sustained receptor activation has been observed in mice carrying targeted G-CSFR mutations corresponding to those in CN patients. 14,15 From these in vitro and in vivo data and from the fact that somatic G-CSFR mutations are frequently detected prior to morphologic evidence of transformation, it has been hypothesized that they represent an important step in the progression of CN to MDS/leukemia. 10,11 Conversion to MDS/leukemia in CN patients has been associated with other cellular genetic abnormalities, for example partial or complete loss of chromosome 7 (7qÀ or monosomy 7), abnormalities of chromosome 21 (trisomy 21), and/or activating RAS mutations, 5,16 which are considered to act as cooperating events in the malignant transformation of leukemic progenitors.…”