Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE (ELA2), HAX1, GFI1, WAS, CSF3R or G6PC3.
Severe congenital neutropenia terminating in acute myeloid leukemia: disease progression associated with mutations in the granulocyte-colony stimulating factor receptor gene.
A novel mutation in the juxtamembrane intracellular sequence of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a patient with severe congenital neutropenia augments GCSF proliferation activity but not through the MAP kinase cascade.
A subgroup of patients with severe congenital neutropenia (SCN) has been shown to harbor mutations in the G-CSF receptor gene that resulted in the truncation of the receptor's carboxyl-terminal region.
Acquired granulocyte colony-stimulating factor receptor mutations are detected in approximately 80% of congenital neutropenia patients who developed acute myeloid leukemia.
Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of patients who had CN and who developed acute myeloid leukemia, suggesting that these mutations are involved in leukemogenesis.
Acquisition of CSF3R mutations is a CN-specific phenomenon and is associated with inherited mutations causing CN or cyclic neutropenia, such as ELANE mutations.
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.
Defective internalization and sustained activation of truncated granulocyte colony-stimulating factor receptor found in severe congenital neutropenia/acute myeloid leukemia.
Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones.
Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment.
Here we report the identification of a somatic point mutation in one allele of the G-CSF receptor gene in a patient with severe congenital neutropenia.
Herein, we report a case of a 5-year-old SCN girl with homozygous c610-611 del ins AG (p.Q204R) mutation in the CSF3R gene, who was successfully treated with granulocyte macrophage colony stimulating factor.
High frequency of acquired <i>CSF3R</i> (colony stimulating factor 3 receptor, granulocyte) mutations has been described in patients with severe congenital neutropenia (CN) at pre-leukemia stage and overt acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Hypotheses underlying our model are: an ELANE mutation causes SCN; CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells with CSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage.
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.