Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte colony-stimulating factor (G-CSF) is a growth factor that regulates the production and function of neutrophils. G-CSF has been used to treat neutropenia in neonates, pediatric cancer patients, and patients undergoing stem cell transplantation. The regulation of transcription factors mediating G-CSF activity has not been well characterized. The goal of this study was to examine the regulation of the ETS binding protein, Friend leukemia integration site 1 (Fli-1), in myeloid cells treated with G-CSF. Fli-1 has oncogenic properties in humans and mice, and plays a role in vascular and hematopoietic cell development. We previously reported that Fli-1 and the serum response factor bind at adjacent sites within the serum response element-1 of the early growth response gene-1 promoter in the murine myeloid leukemic cell line, NFS60. We also identified that Fli-1 DNA binding increased in G-CSF-treated cells compared with untreated cells. To determine whether the change in binding activity is due to increased Fli-1 transcription or protein stability, we examined endogenous Fli-1 expression in G-CSF-treated or -untreated NFS60 cells. Our results demonstrated that levels of Fli-1 protein, but not RNA, were higher in extracts from cells treated with G-CSF. The increase in Fli-1 protein was also dependent on protein synthesis. Finally, we showed that the half-life of Fli-1 is prolonged in G-CSF-treated cells compared with control-treated cells. These results suggest that G-CSF induces stabilization of Fli-1 protein in myeloid cells, thus proposing a novel mechanism by which hematopoietic growth factors regulate transcription factors.
 ...
PMID:G-CSF induces stabilization of ETS protein Fli-1 during myeloid cell development. 1555 8

Background. The phenotypes of patients with the recently discovered, dominant, ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. Patients and Methods. Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with ETV6 germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits. Results. Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of ETV6 (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in RUNX1 (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of 'immune' thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of ETV6 (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in ARID5B (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects. Conclusions. Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with ETV6 germline mutations. Further, we propose ARID5B as potential leukaemogenic cofactor in patients with ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome.
 ...
PMID:Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor. 3170 77