Discovering early molecular determinants of leukemogenesis

Department of Medicine and Molecular and Medical Genetics, Oregon Health and Sciences University, Oregon, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 04/2008; 118(3):847-50. DOI: 10.1172/JCI35109
Source: PubMed


Truncating mutations of the G-CSF receptor are found during disease course in nearly half of all patients with severe congenital neutropenia. In this issue of the JCI, Liu et al. demonstrate that these mutations confer a competitive clonal advantage upon HSCs in mice and that the advantage is conditional because it is observed only in the presence of the ligand G-CSF (see the related article beginning on page 946). Once activated, the mutant receptor requires the function of Stat5 in order to effect clonal expansion of this stem cell population. The results support the notion that early molecular steps in this and other neoplastic processes represent adaptations in which, through somatic mutations, "unfit" stem cells gain a measure of fitness by altering their relationships with their microenvironment.

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    • "We still do not understand the relationship of defective DNA repair to progressive bone marrow failure, even though we know that this phenotype arises from impaired selfrenewal of hematopoietic stem cells (Carreau et al., 1999). Additional defects not easily understood from defects in DNA repair, include poor resistance to oxidative damage, interaction with inflammation pathways, and hyperactivation of the MAPK pathway leading to overproduction of TNF-a (Bagby, 2008; Briot et al., 2008; Li et al., 2007; Sejas et al., 2007; Uziel et al., 2008). At least some of these difficult to explain phenotypes may involve key functions of FANCs distinct from the NC complex. "
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    • "Recently we found that G-CSF-treated myeloid progenitor cells from CN patients expressed high levels of activated phospho-STAT5 protein (Skokowa et al, 2007; Germeshausen et al, 2008b). This data was further confirmed by findings in a recently published mouse model (Liu et al, 2008) demonstrating that CSF3R mutations confer a strong clonal advantage of hematopoietic stem cells via activation of STAT5 that is depending on exogenous G-CSF (Liu et al, 2008; Bagby 2008). Therefore, one possible mechanism of leukemogenesis could be the prolonged activation of STAT5 in CSF3R mutation-bearing cells rendering them to additional molecular aberrations. "
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    ABSTRACT: Congenital Neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte/myelocyte stage with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l. There are two major subtypes of CN as judged by inheritance: an autosomal dominant subtype, e.g. defined by neutrophil elastase mutations (approximately 60% of patients) and an autosomal recessive subtype (approximately 30% of patients), both presenting with the same clinical and morphological phenotype. Different mutations have been described (e.g. HAX1, p14 etc) in autosomal recessive CN, with HAX1 mutations in the majority of these patients. CN in common is considered as a preleukemic syndrome, since the cumulative incidence for leukemia is more than 25% after 20 years of observation. Leukemias occur in both, the autosomal dominant and recessive subtypes of CN. The individual risk for each genetic subtype needs to be further evaluated. Numbers of patients tested for the underlying genetic defect are still limited. Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of CN patients who developed acute myeloid leukemia independent of the ELA2 or HAX1 genetic subtype, suggesting that these mutations are involved in leukemogenesis. As the majority of patients benefit from G-CSF administration, HSCT should be restricted to non-responders and patients with leukaemic transformation.
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