title: Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia.
abstract: RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFbeta-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFbeta-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML.
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Chi Keung
authors.initials: CK
authors.lastname: Cheng
authors.forename: Libby
authors.initials: L
authors.lastname: Li
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Kin Mang
authors.initials: KM
authors.lastname: Lau
authors.forename: Natalie P H
authors.initials: NP
authors.lastname: Chan
authors.forename: Raymond S M
authors.initials: RS
authors.lastname: Wong
authors.forename: Matthew M K
authors.initials: MM
authors.lastname: Shing
authors.forename: Chi Kong
authors.initials: CK
authors.lastname: Li
authors.forename: Margaret H L
authors.initials: MH
authors.lastname: Ng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D014158:Transcription, Genetic; D014178:Translocation, Genetic
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human