The GFI1 gene encodes a transcriptional repressor, which regulates myeloid differentiation. In the mouse, Gfi1 deficiency causes neutropenia and an accumulation of granulomonocytic precursor cells that is reminiscent of a myelodysplastic syndrome. We report here that a variant allele of GFI1 (GFI1 36N ) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 ؋ 10 ؊5 ). The GFI1 36N variant occurred in 1806 AML patients with an allele frequency of 0.055 compared with 0.035 in 1691 healthy control patients in 2 independent cohorts. We observed that both GFI1 variants maintain the same activity as transcriptional repressors but differ in their regulation by the AML1/ETO (RUNX1/RUNX1T1) fusion protein produced in AML patients with a t(8;21) translocation. AML1/ETO interacts and colocalizes with the more common GFI1 36S form in the nucleus and inhibits its repressor activity. However, the variant GFI1 36N protein has a different subnuclear localization than GFI1 36S . As a consequence, AML1/ETO does not colocalize with GFI1 36N and is unable to inhibit its repressor activity. We conclude that both variants of GFI1 differ in their ability to be regulated by interacting proteins and that the GFI1 36N variant form exhibits distinct biochemical features that may confer a predisposition to AML. (Blood.

Saliva secreted during caterpillar feeding contains enzymes to initiate digestion or detoxify noxious plant compounds. Activity of some salivary enzymes is diet-dependent and may be transcriptionally regulated. In this study, cDNA-amplified fragment length polymorphism was used to identify beet armyworm, Spodoptera exigua Hübner, labial salivary genes that are differentially expressed in response to diet. In addition, SeGOX was sequenced based on homology and characterized to confirm that the transcript encodes a functional enzyme. Three labial salivary transcripts, encoding glucose oxidase (GOX) and two proteins of unknown function (Se1H and Se2J), were expressed in a diet-specific manner. Since diet, particularly the protein to digestible carbohydrate levels and ratio, may affect labial salivary enzyme activity, the influence of nutritional quality on gene expression was determined. Transcript levels of the labial salivary genes Se1H, Se2J and SeGOX increased with dietary carbohydrate levels, regardless of protein concentrations. In contrast GOX enzymatic activity increased with increasing dietary carbohydrates when caterpillars were fed protein-rich diets, but not when caterpillars were fed protein-poor diets. Our results suggest that dietary carbohydrates affect SeGOX, Se1H and Se2J transcription, but dietary protein or amino acid levels affect translational and/or post-translational regulation of the enzyme GOX.

The primary function of salivary glands is fluid and protein secretion during feeding. Compared to mammalian systems, little is known about salivary protein secretion processes and the effect of diet on the salivary proteome in insect models. Therefore, the effect of diet nutritional quality on caterpillar labial salivary gland proteins was investigated using an unbiased global proteomic approach by nanoLC/ESI/tandem MS. Caterpillars of the beet armyworm, Spodoptera exigua Hübner, were fed one of three diets: an artificial diet containing their self-selected protein to carbohydrate (p:c) ratio (22p:20c), an artificial diet containing a higher nutritional content but the same p:c ratio (33p:30c) or the plant Medicago truncatula Gaertn. As expected, most identified proteins were associated with secretory processes and not influenced by diet. However, some diet-specific differences were observed. Nutrient stress-associated proteins, such as peptidyl-propyl cis-trans isomerase and glucose-regulated protein94/endoplasmin, and glyceraldehyde 3-phosphate dehydrogenase were identified in the labial salivary glands of caterpillars fed nutritionally poor diets, suggesting a link between nutritional status and vesicular exocytosis. Heat shock proteins and proteins involved in endoplasmic reticulum-associated protein degradation were also abundant in the labial salivary glands of these caterpillars. In comparison, proteins associated with development, such as arylphorin, were found in labial salivary glands of caterpillars fed 33p:30c. These results suggest that caterpillars fed balanced or nutritionally-poor diets have accelerated secretion pathways compared to those fed a protein-rich diet.

No abstract