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

Abstract

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.

ETS1 phosphorylation at threonine 38 is associated with the cell of origin of diffuse large B cell lymphoma and sustains the growth of tumour cells

“…In several cancer types there, is a significant higher or exclusive ETS1 expression when compared to normal tissues as a demonstration of a direct involvement in tumorigenesis and/or drug resistance. [41][42][43][44][45] Interfering with ETS1 phosphorylation could be worth of being investigated in DLBCL as well in other tumours.…”

“…More in general, in B cells ETS1 can activate the Igμ heavy chain enhancer 36–39 and lead to PAX5 up‐regulation, 40 in this way negatively regulating plasmacytic differentiation. In several cancer types there, is a significant higher or exclusive ETS1 expression when compared to normal tissues as a demonstration of a direct involvement in tumorigenesis and/or drug resistance 41–45 . Interfering with ETS1 phosphorylation could be worth of being investigated in DLBCL as well in other tumours.…”