eprintid: 10110061
rev_number: 21
eprint_status: archive
userid: 608
dir: disk0/10/11/00/61
datestamp: 2020-09-15 09:58:39
lastmod: 2021-12-07 23:56:17
status_changed: 2020-09-15 09:58:39
type: article
metadata_visibility: show
creators_name: Solanki, A
creators_name: Yánez, DC
creators_name: Lau, C-I
creators_name: Rowell, J
creators_name: Barbarulo, A
creators_name: Ross, S
creators_name: Sahni, H
creators_name: Crompton, T
title: The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation
ispublished: inpress
divisions: UCL
divisions: B02
divisions: C08
divisions: D09
divisions: D13
divisions: G24
note: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
abstract: Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL.
date: 2020-09-09
date_type: published
publisher: The Company of Biologists
official_url: https://doi.org/10.1242/dev.192203
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1812955
doi: 10.1242/dev.192203
lyricists_name: Crompton, Tessa
lyricists_name: Ross, Susan
lyricists_name: Rowell, Jasmine
lyricists_name: Yanez Marcayata, Diana
lyricists_id: TCROM00
lyricists_id: SEROS53
lyricists_id: JEROW76
lyricists_id: YANEZ87
actors_name: Austen, Jennifer
actors_id: JAUST66
actors_role: owner
full_text_status: public
publication: Development
citation:        Solanki, A;    Yánez, DC;    Lau, C-I;    Rowell, J;    Barbarulo, A;    Ross, S;    Sahni, H;           Solanki, A;  Yánez, DC;  Lau, C-I;  Rowell, J;  Barbarulo, A;  Ross, S;  Sahni, H;  Crompton, T;   - view fewer <#>    (2020)    The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation.                   Development        10.1242/dev.192203 <https://doi.org/10.1242/dev.192203>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10110061/1/dev.192203.full.pdf