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Acute myeloid leukemia

Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation

Leukemia volume 33, pages 1822–1827 (2019)Cite this article

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The AML1-ETO fusion protein is produced by the t(8;21) translocation, which is the most common chromosomal abnormality in acute myeloid leukemia (AML). Although AML1-ETO alone is insufficient to cause leukemia, it is necessary for maintaining leukemia and therefore represents a therapeutic target. This notion has been supported by several lines of evidence: (i) transient suppression of AML1-ETO by small interfering RNA (siRNA) increases susceptibility of the leukemic cells to differentiation and delays leukemogenesis in vivo [1, 2]; (ii) in a mouse model harboring fully developed leukemia, switching off AML1-ETO leads to leukemia regression [3]; (iii) in an AML1-ETO9a (AE9a)-driven leukemic mouse model, myeloid differentiation of leukemic cells triggered by panobinostat (an HDAC inhibitor) was attributed to AE9a degradation[4]; and (iv) mechanistic studies revealed that depletion of AML1-ETO in leukemic cells leads to a genome-wide epigenetic reprogramming and changes in transcription factor binding, resulting in myeloid differentiation and loss of leukemia maintenance [5].

We previously found that, in leukemic cells, AML1-ETO is stabilized and functions through the AML1-ETO-containing transcription factor complex (AETFC), which contains multiple transcription (co)factors that include AML1-ETO, CBFβ, E proteins HEB and E2A, hematopoietic bHLH transcription factor LYL1, LIM domain protein LMO2 and its binding partner LDB1 [6]. These AETFC components mutually stabilize each other and cooperatively bind and regulate target genes, and AETFC integrity and proper conformation are essential for leukemogenesis [6]. Thus, destabilization of AETFC provides a strategy to target AML1-ETO. Notably, it has been generally proposed that the stability of a protein complex can be reflected by its sensitivity to overexpression versus depletion of individual components [7]. First, many complexes can be destabilized by overexpression of individual components that, in a dosage-dependent manner, make promiscuous interactions that change the topology of the complex and thereby destabilize it. This mechanism, known as “dosage sensitivity”, is widely applicable to the regulation of protein functions in organisms ranging from yeast to human [8], including the interplay among the key transcription factors in hematopoiesis and leukemogenesis [9]. Second, other complexes show a lack of sensitivity (termed “robustness”) to component overexpression, likely because they possess strong multivalent interactions that cannot be altered by dosage increase, but can be perturbed by depletion, of individual components [10].

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Acknowledgements

This work was supported by the National Key Research and Development Plan of China 2018YFA0107802 (X-JS) and 2018YFA0107202 (LW), the Chinese Academy of Sciences (CAS) Bureau of Frontier Sciences and Education Program QYZDBSSW-SMC027 (L.W.), the National Natural Science Foundation of China (NSFC) General Program 81470316, 81670094 (X-JS), 81670149 (Q-HH), 81470334, 81670122 (LW), 81270623 (SS) and Youth Program 81500080 (Y-LZ), the NSFC Excellent Young Scholar Program 81622003 (LW), the Chinese National Key Basic Research Project 2013CB966801 (X-JS), the National Key Research and Development Plan of China 2016YFC0902202 (LW), the National Institutes of Health (NIH) of USA R01 grants CA163086, CA178765 (RGR) and CA166835 (SDN), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant 20152506 (X-JS), the CAS Bureau of Major R&D Program XDA12020376 (LW), the fourth round of Three Year Public Health Action Plan GWIV-25 (SS), the Shanghai Municipal Science and Technology Major Project 2017SHZDZX01 (FL), the 111 Project B17029 (X-JS, RGR, and S-JC), and the Samuel Waxman Cancer Research Foundation. X-JS and LW were supported by the 1000 Talents Program for Young Scholars. We thank Y. Zhai, X. Miao, S. Yan, Y. Chen, K. Wang and Y. Wang at the Shanghai Institute of Nutrition and Health core facilities for technical support.

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  1. These author contributed equally: Meng-Meng Zhang, Na Liu and Yuan-Liang Zhang

Authors and Affiliations

  1. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Meng-Meng Zhang, Yuan-Liang Zhang, Xiao-Lin Wang, Yin-Yin Xie, Jiang Zhu, Zhu Chen, Sai-Juan Chen, Qiu-Hua Huang & Xiao-Jian Sun

  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Na Liu, Chun-Hui Xu & Lan Wang

  3. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Epigenetics and Metabolism, Ministry of Science and Technology, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Bowen Rong & Fei Lan

  4. Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Shuhong Shen

  5. Department of Biochemistry and Molecular Biology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Stephen D. Nimer

  6. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA

    Robert G. Roeder

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Correspondence to Lan Wang, Qiu-Hua Huang or Xiao-Jian Sun.

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Data deposition: The RNA-seq and ChIP-seq data have been deposited in the Gene Expression Omnibus (GEO) database and are accessible through GEO series number GSE114642.

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Zhang, MM., Liu, N., Zhang, YL. et al. Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation. Leukemia 33, 1822–1827 (2019). https://doi.org/10.1038/s41375-019-0398-8

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