Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, IL.
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY.
Blood Adv. 2022 Oct 25;6(20):5613-5624. doi: 10.1182/bloodadvances.2022007725.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell lymphoma associated with the human T-cell lymphotropic virus type 1 virus endemic in regions including Japan, the Caribbean islands, and Latin America. Although progress has been made to understand the disease, survival outcomes with current standard therapy remain extremely poor particularly in acute ATLL, underlying the need for better understanding of its biology and identification of novel therapeutic targets. Recently, it was demonstrated that ATLL of North American-descendent patients (NA-ATLL) is both clinically and molecularly distinct from Japanese-descendent (J-ATLL), with inferior prognosis and higher incidence of epigenetic-targeting mutations compared with J-ATLL. In this study, combined chromatin accessibility and transcriptomic profiling were used to further understand the key transcriptional regulators of NA-ATLL compared with J-ATLL. The ETS1 motif was found to be enriched in chromatin regions that were differentially open in NA-ATLL, whereas the AP1/IRF4 motifs were enriched in chromatin regions more open in J-ATLL. ETS1 expression was markedly elevated in NA-ATLL in both cell line and primary tumor samples, and knockdown of ETS1 in NA-ATLL cells resulted in inhibition of cell growth. CCR4, a previously identified oncogenic factor in ATLL, was found to be a direct ETS1 transcriptional target in NA-ATLL. As such, ETS1 provides an alternate mechanism to enhance CCR4 expression/activity in NA-ATLL, even in the absence of activating CCR4 mutations (CCR4 mutations were identified in 4 of 9 NA-ATLL cases). Taken together, this study identifies ETS1 as a novel dominant oncogenic transcriptional regulator in NA-ATLL.
成人 T 细胞白血病/淋巴瘤（ATLL）是一种侵袭性 T 细胞淋巴瘤，与人类 T 细胞白血病病毒 1 型病毒有关，该病毒在包括日本、加勒比海岛屿和拉丁美洲在内的地区流行。尽管人们在了解这种疾病方面取得了进展，但目前标准治疗的生存结果仍然非常差，尤其是在急性 ATLL 中，这凸显了更好地了解其生物学特性和确定新的治疗靶点的必要性。最近，人们证明了北美人起源的 ATLL（NA-ATLL）在临床和分子上与日本人起源的 ATLL（J-ATLL）不同，与 J-ATLL 相比，其预后更差，表观遗传靶向突变的发生率更高。在这项研究中，联合染色质可及性和转录组谱分析用于进一步了解与 J-ATLL 相比，NA-ATLL 的关键转录调节因子。发现在 NA-ATLL 中差异开放的染色质区域中富集了 ETS1 基序，而在 J-ATLL 中更开放的染色质区域中富集了 AP1/IRF4 基序。在 NA-ATLL 的细胞系和原发性肿瘤样本中，ETS1 的表达明显升高，并且在 NA-ATLL 细胞中敲低 ETS1 导致细胞生长受到抑制。CCR4 是 ATLL 中先前鉴定的致癌因子，在 NA-ATLL 中被发现是 ETS1 的直接转录靶标。因此，ETS1 提供了一种替代机制，可增强 NA-ATLL 中 CCR4 的表达/活性，即使在没有激活 CCR4 突变的情况下（在 9 例 NA-ATLL 病例中发现了 4 例 CCR4 突变）。综上所述，这项研究确定 ETS1 为 NA-ATLL 中的一种新型优势致癌转录调节因子。
