Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.
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ABSTRACT:
SUBMITTER: Zhang MM
PROVIDER: S-EPMC6880927 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.
Zhang Meng-Meng MM Liu Na N Zhang Yuan-Liang YL Rong Bowen B Wang Xiao-Lin XL Xu Chun-Hui CH Xie Yin-Yin YY Shen Shuhong S Zhu Jiang J Nimer Stephen D SD Chen Zhu Z Chen Sai-Juan SJ Roeder Robert G RG Lan Fei F Wang Lan L Huang Qiu-Hua QH Sun Xiao-Jian XJ
Leukemia 20190212 7
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2019-02-19 | GSE114642 | GEO
Project description:Destabilization of AETFC through C/EBPalpha-mediated repression of LYL1 contributes to t(8 21) leukemic cell differentiation
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Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components colocalize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, CBFβ, HEB, E2A, LYL1, LMO2, and LDB1) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.
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