ETS1 is a novel transcriptional regulator of adult T-cell leukemia/lymphoma of North American descent.

Autor:	Luchtel RA; Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, IL., Zhao Y; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY., Aggarwal RK; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY., Pradhan K; Department of Epidemiology & Population Health (Biostatistics), Albert Einstein College of Medicine, Bronx, NY., Maqbool SB; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Oct 25; Vol. 6 (20), pp. 5613-5624.
DOI:	10.1182/bloodadvances.2022007725
Abstrakt:	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. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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