Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey.
Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey.
Blood Cancer Discov. 2021 Jan;2(1):92-109. doi: 10.1158/2643-3230.BCD-20-0201. Epub 2020 Nov 24.
Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the promoter in multiple hematopoietic populations, including T-cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced levels in T-ALL cells. Moreover, PE-null mice show reduced levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.
长距离致癌增强子在癌症中起着重要作用。然而，肿瘤抑制基因是否存在类似的调节尚不清楚。PTEN 的表达缺失与各种癌症的发病机制有关，包括 T 细胞白血病（T-ALL）。在这里，我们鉴定了一个高度保守的远端增强子（PE），它与多种造血细胞中的启动子相互作用，包括 T 细胞，并作为 T-ALL 中相关转录因子的中心。一致地，PE 的缺失导致 T-ALL 细胞中水平降低。此外，PE 缺失的小鼠在胸腺细胞中显示出水平降低，并加速了 NOTCH1 诱导的 T-ALL 的发展。此外，在已建立的白血病中二次缺失 PE 会导致加速进展和由基因表达特征驱动的白血病。最后，我们在 T-ALL 中发现了包含 PE 的反复缺失，这与水平降低有关。总之，我们的研究结果确定了 PE 作为第一个直接参与癌症的长距离肿瘤抑制增强子。
