title: Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia.
abstract: 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.
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Russell C
authors.initials: RC
authors.lastname: DeKelver
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lewin
authors.forename: Kentson
authors.initials: K
authors.lastname: Lam
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Chandler
authors.initials: C
authors.lastname: Rundle
authors.forename: Miao-Chia
authors.initials: MC
authors.lastname: Lo
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human