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Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
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نویسنده
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dekelver r.c. ,lewin b. ,lam k. ,komeno y. ,yan m. ,rundle c. ,lo m.-c. ,zhang d.-e.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 10
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چکیده
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Fusion protein runx1-eto (aml1-eto,runx1-runx1t1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)],which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. runx1-eto is thought to promote leukemia development through the aberrant regulation of runx1 (aml1) target genes. repression of these genes occurs via the recruitment of the corepressors n-cor and smrt due to their interaction with eto. mechanisms of runx1-eto target gene upregulation remain less well understood. here we show that runx1-eto9a,the leukemogenic alternatively spliced transcript expressed from t(8;21),upregulates target gene alox5,which is a gene critically required for the promotion of chronic myeloid leukemia development by bcr-abl. loss of alox5 expression reduces activity of runx1-eto9a,mll-af9 and pml-rarα in vitro. however,alox5 is not essential for the induction of leukemia by runx1-eto9a in vivo. finally,we demonstrate that the upregulation of alox5 by runx1-eto9a occurs via the c2h2 zinc finger transcription factor klf6,a protein required for early hematopoiesis and yolk sac development. furthermore,klf6 is specifically upregulated by runx1-eto in human leukemia cells. this identifies klf6 as a novel mediator of t(8;21) target gene regulation,providing a new mechanism for runx1-eto transcriptional control. © 2013 dekelver et al.
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آدرس
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division of biological sciences,university of california san diego,la jolla,ca, United States, division of biological sciences,university of california san diego,la jolla,ca, United States, department of biomedical sciences,university of california san diego,la jolla,ca, United States, moores cancer center,university of california san diego,la jolla,ca, United States, moores cancer center,university of california san diego,la jolla,ca, United States, division of biological sciences,university of california san diego,la jolla,ca, United States, moores cancer center,university of california san diego,la jolla,ca, United States, division of biological sciences,university of california san diego,la jolla,ca,united states,department of biomedical sciences,university of california san diego,la jolla,ca,united states,moores cancer center,university of california san diego,la jolla,ca,united states,department of pathology,university of california san diego,la jolla,ca, United States
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Authors
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