2. Academic Validation
  3. The epigenetic regulators EP300/CREBBP represent promising therapeutic targets in MLL-rearranged acute myeloid leukemia

The epigenetic regulators EP300/CREBBP represent promising therapeutic targets in MLL-rearranged acute myeloid leukemia

  • Cell Death Discov. 2024 May 1;10(1):206. doi: 10.1038/s41420-024-01940-5.
Wenqi Wu # 1,  Yanan Jiang # 2,  Donghui Xing # 1,  Yixin Zhai 1,  Huimeng Sun 1,  Xiang He 1,  Kaiping Luo 1,  Pengpeng Xu 3,  Feng Pan 4,  Guolei Dong 5,  Guibing Ren 6,  Zhigang Zhao 7
Affiliations

Affiliations

  • 1 Department of Senior ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 2 Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine. Nankai University, Tianjin, 300192, China.
  • 3 Department of Oncology, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, 300162, China.
  • 4 Department of Molecular Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3904, USA.
  • 5 Department of Breast Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. nkdongguolei@163.com.
  • 6 Department of Oncology, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, 300162, China. renguibing1972@163.com.
  • 7 Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine. Nankai University, Tianjin, 300192, China. zzhao01@tmu.edu.cn.
  • # Contributed equally.
PMID: 38693103 DOI: 10.1038/s41420-024-01940-5
Abstract

Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangements (MLL-r) is an aggressive subtype of blood Cancer with dismal prognosis, underscoring the urgent need for novel therapeutic strategies. E1A-binding protein (EP300) and CREB-binding protein (CREBBP) function as essential transcriptional coactivators and acetyltransferases, governing leukemogenesis through diverse mechanisms. Targeting EP300/CREBBP holds great promise for treating leukemia with some certain cytogenetic abnormalities. Here, we demonstrated that EP300 and CREBBP are core epigenetic regulators in the pathogenesis of MLL-r AML through assaying the transposase-accessible chromatin with high-throughput Sequencing (ATAC-seq). Knocking-out EP300/CREBBP and inhibitor (A-485) treatment depressed the MLL-r cells proliferation, while the MLL wild-type cells remained uninfluenced. We found that the CDK4/RB/E2F axis was downregulated specifically in MLL-r AML cell after A-485 treatment by RNA-seq, western blot and cut-tag analyses. EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.

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