Nature - 2019.08.29

RESEARCH LETTER

BRD4, which rendered the resistant cells more sensitive to BET inhi-

bition (Extended Data Fig. 9; Supplementary Note 2). Together, these

results indicate the establishment of an alternative transcription factor

regulatory network controlled by BORIS-induced chromatin remod-

elling to support the resistant cell state.

Thus, using a pair of isogenic ALK-inhibitor sensitive and resistant

neuroblastoma cell lines, we show that the CTCF paralogue BORIS

can promote regulatory DNA interactions that support a phenotypic

switch in the context of treatment resistance (Fig. 4e). This mechanism

appears relevant to different neuroblastoma cell lines and kinase inhib-

itors and may extend to other cancers. In Ewing sarcoma, in which

overexpression of BORIS is associated with metastasis and relapse

(Extended Data Fig. 1c), we observed increased BORIS occupancy at

regulatory regions in chemotherapy-resistant cell lines (Extended Data

Fig. 10; Supplementary Note 3). Further work will establish whether

BORIS-mediated alteration of chromatin looping is a general mecha-

nism by which tumour cells co-opt developmental networks to sustain

alternative cell states in response to targeted or conventional therapies.

Online content

Any methods, additional references, Nature Research reporting summaries,

source data, extended data, supplementary information, acknowledgements,

peer review information; details of author contributions and competing

interests; and statements of data and code availability are available at https://doi.org/

10.1038/s41586-019-1472-0.

Received: 21 July 2017; Accepted: 11 July 2019;

Published online 7 August 2019.

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