Submitted February 5, 2008
Accepted June 29, 2008
Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia
Chi Keung Cheng, Libby Li, Suk Hang Cheng, Kin Mang Lau, Natalie PH Chan, Raymond SM Wong, Matthew MK Shing, Chi Kong Li, and Margaret HL Ng*
A & C Pathology, CUHK, Hong Kong, Hong Kong
Medicine & Therapeutics, CUHK, Hong Kong, Hong Kong
Pediatrics, CUHK, Hong Kong, Hong Kong
State Key Laboratory in Oncology in South China, The CUHK, Hong Kong, Hong Kong
* Corresponding author; email: margaretng{at}cuhk.edu.hk.
RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by two 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 CBF
-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 two conserved RUNX binding sites in the P1 promoter. In in-vitro studies, ectopically expressed RUNX1-ETO and CBF-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.
