C11orf21, a novel RUNX1 target gene, is down-regulated by RUNX1-ETO

Akifumi Matsumoto; Tatsushi Yoshida; Takahiro Shima; Kenta Yamasaki; Kenjiro Tadagaki; Noriko Kondo; Yasumichi Kuwahara; Dong-Er Zhang; Tsukasa Okuda

doi:10.1016/j.bbadva.2022.100047

C11orf21, a novel RUNX1 target gene, is down-regulated by RUNX1-ETO

BBA Adv. 2022 Feb 25:2:100047. doi: 10.1016/j.bbadva.2022.100047. eCollection 2022.

Authors

Akifumi Matsumoto¹, Tatsushi Yoshida¹, Takahiro Shima^{2

3}, Kenta Yamasaki¹, Kenjiro Tadagaki¹, Noriko Kondo¹, Yasumichi Kuwahara¹, Dong-Er Zhang², Tsukasa Okuda¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
² Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
³ Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Abstract

The fusion protein RUNX1-ETO is an oncogenic transcription factor generated by t(8;21) chromosome translocation, which is found in FAB-M2-type acute myeloid leukemia (AML). RUNX1-ETO is known to dysregulate the normal RUNX1 transcriptional network, which should involve essential factors for the onset of AML with t(8;21). In this study, we screened for possible transcriptional targets of RUNX1 by reanalysis of public data in silico, and identified C11orf21 as a novel RUNX1 target gene because its expression was down-regulated in the presence of RUNX1-ETO. The expression level of C11orf21 was low in AML patient samples with t(8;21) and in Kasumi-1 cells, which carry RUNX1-ETO. Knockdown of RUNX1-ETO in Kasumi-1 cells restored C11orf21 expression, whereas overexpression of RUNX1 up-regulated C11orf21 expression. In addition, knockdown of RUNX1 in other human leukemia cells without RUNX-ETO, such as K562, led to a decrease in C11orf21 expression. Of note, the C11orf21 promoter sequence contains a consensus sequence for RUNX1 binding and it was activated by exogenously expressed RUNX1 based on our luciferase reporter assay. This luciferase signal was trans-dominantly suppressed by RUNX1-ETO and site-directed mutagenesis of the consensus site abrogated the reporter activity. This study demonstrated that C11orf21 is a novel transcriptional target of RUNX1 and RUNX1-ETO suppressed C11orf21 transcription in t(8;21) AML. Thus, through this in silico approach, we identified a novel transcriptional target of RUNX1, and the depletion of C11orf21, the target gene, may be associated with the onset of t(8;21) AML.

Keywords: C11orf21; RNA-seq; RUNX1; RUNX1-ETO; t(8:21) AML.