[Granulopoeisis and leukemogenesis: lessons from congenital neutropenia]

Congenital neutropenia are extremely rare diseases, defined by a permanent or cyclic decrease of blood neutrophils. Molecular basis of several congenital neutropenia has been recently determined, involving gene coding for the neutrophil elastase gene (ELA2), GFI1, WAS protein and mitochondrial HAX1 protein. These mutations, dominant (ELA2, GFI1), X-linked (WAS) and autosomal recessive (HAX1), result in instability of the contents of the granules- particularly the neutrophil elastase- or in abnormalities of the cytoskeleton, and possibly, in an increased apoptosis. ELA2 mutations resulting both in profound and permanent neutropenia, and in cyclic--pseudo sinusoidal--neutropenia lead to consider that time pattern is very close in the two apparently distinct phenotypes. This observation suggests that temporal variations of neutrophils could be represented by non linear functions. Congenital neutropenia, specifically ELA2 mutated, are also characterized by a high rate of leukemia (about 15% at 20 years of age). Leukemia risk does not appear to be related to an oncogenic effect of ELA2 mutations, but much likely to the deepness of the neutropenia, and the intensity of G-CSF therapy.