Friend leukemia

About: Friend leukemia is a research topic. Over the lifetime, 319 publications have been published within this topic receiving 7463 citations.

Retroviral Insertions Downstream oftheHeterogeneous Nuclear Ribonucleoprotein AlGeneinErythroleukemia Cells: Evidence that AlIsNotEssential forCellGrowth

Abstract: A large numberofnovel cellular proto-oncogenes havebeenidentified andcloned byanalysis ofcommon integration sites inretrovirally induced malignancies. Inthemultistage erythroleukemias induced bythe various strains ofFriend leukemia virus, theanalysis ofproviral-integration events hasledtotheidentification oftwogenes, Fli-1 andSpi-1, bothnovel membersoftheetsoncogene family oftranscription factors. Inthis report, wedescribe theidentification ofanother integration site, designated Fli-2 (Friend leukemia virus integration-2), inanerythroleukemia celllineinduced byFriendmurineleukemia virus(F-MuLV). Rearrangements attheFli-2 locus werefoundintwoerythroleukemia cell lines independently induced by F-MuLVandoneleukemic cell line derived fromthespleen ofamouseinfected withthepolycythemia strain ofFriend leukemia virus. Thededuced aminoacidsequence ofa cDNAcorresponding toa transcript originating fromgenomic DNA adjacent toFli-2 isidentical tothatofthehumanheterogeneous nuclear ribonucleoprotein Algene, amemberofthegenefamily ofRNA-binding proteins involved inRNA splicing. Inoneerythroleukemia cell line, Alexpression wasundetectable asaresult ofF-MuLVintegration inoneallele andloss oftheother allele. These results suggest that perturbations inRNAsplicing mechanisms maycontribute tomalignant transformation andprovide direct evidence that theAlprotein isnotrequired forcell growth. Friend leukemia isa multistage malignancy associated withanearly stage characterized bythepolyclonal proliferation ofinfected erythroid progenitors followed byaleukemicstage inwhicherythroleukemia cell clones emerge(2, 17). Theearly andlate stages ofFriend leukemia canbe induced following asingle injection ofeither thepolycythemia-oranemia-inducing strain ofFriend leukemia virus (FV-PorFV-A,respectively). BothFV-PandFV-Aare complexes of a defective spleenfocus-forming virus (SFFV-P andSFFV-A,respectively) andareplication-competent Friend murineleukemia virus (F-MuLV). F-MuLV itself canalsoinduce erythroleukemia wheninjected into newborn miceofcertain susceptible strains (34). We havepreviously shownthat thetumorsuppressor gene p53isinactivated inalmost alloftheerythroleukemia cell lines induced byvarious strains ofFriend leukemia virus, as aresult ofdeletion, truncation, retrovirus insertion, orpoint mutation (2, 27,28). Moreau-Gachelin etal.haveidentified a commonsite forretroviral integration namedSpi-1 (SFFV provirus integration-1) andshownthatthislocusisrearranged inthemajority oftheerythroleukemia celllines induced bytheFV-PandFV-Astrains ofFriend leukemia virus (24, 25). DNA sequences whoseexpression ishighly activated asaresult oftheseSFFVinsertions havebeen isolated- immediately adjacent totheSpi-1 insertion sites (26). Thesequence ofSpi-1 transcripts isidentical tothat of PU.1,agenethat encodes aDNA-binding protein related to

ETS-Related Gene (ERG) and Friend leukemia integration – 1 (FLI-1) Transcription Factors in the Precision Treatment of Pulmonary Arterial Hypertension and Pulmonary Fibrosis

Abstract: Pulmonary arterial hypertension (PAH) is a chronic debilitating cardiopulmonary disease characterized by abnormal remodeling of peripheral lung vasculature resulting in progressive vasoconstriction. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible disease that is often associated with significant morbidity and poor quality of life. The prognosis of PAH and IPF is poor and currently available medications focus on relieving symptoms and slowing down progression. Hence, there is a clear necessity to develop new therapies. ETS-related genes and Friend leukemia integration–1 (FLI–1) are transcription factors involved in angiogenesis, cellular homeostasis, vascular remodeling, and the genetic regulation of inflammation, apoptosis, and fibrosis seen in PAH and IPF. Simultaneous small-interfering-RNA (siRNA) knockdown of ERG and FLI1 in human pulmonary artery endothelial cells (HPAEC) and human pulmonary microvasculature endothelial cells (HPMEC) has been associated with up-regulation of pro-inflammatory genes and interferon (IFN) pathway-related genes. Notably, the endothelium in normal lungs has also been shown to have high levels of nuclear ERG and Fli-1 compared to significantly lower levels in diseased lungs. Recently, ERG upregulation was found to promote liver homoeostasis by regulating canonical TGFβ1SMAD signaling and promoting the SMAD1 pathway while repressing SMAD3 activity. Improvement in pulmonary fibrosis through medications that suppress the TGF-β1/Smad3 pathway has also been a subject of study. In this review, we hypothesize that targeting the regulation of ERG, FLI-1 and ERG-mediation of TGF-β1/Smad3 signaling may be a promising therapeutic strategy in PAH and IPF. Keyword: Pulmonary Diseases, ETS genes, Signaling pathways, Targeted therapy, small molecules, Smad3 inhibitors, ERG/Fli-1 inducers.