eprintid: 10052344
rev_number: 22
eprint_status: archive
userid: 608
dir: disk0/10/05/23/44
datestamp: 2018-07-17 09:33:47
lastmod: 2021-10-08 21:41:36
status_changed: 2018-07-17 09:33:47
type: article
metadata_visibility: show
creators_name: Siriboonpiputtana, T
creators_name: Zeisig, BB
creators_name: Zarowiecki, M
creators_name: Fung, TK
creators_name: Mallardo, M
creators_name: Tsai, CT
creators_name: Lau, PNI
creators_name: Hoang, QC
creators_name: Veiga, P
creators_name: Barnes, J
creators_name: Lynn, C
creators_name: Wilson, A
creators_name: Lenhard, B
creators_name: So, CWE
title: Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: K71
keywords: Cells Of Origin, Hoxa9, MLL Leukemia, Prmt1, Wnt/Β‐Catenin
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: While β‐catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows β‐catenin‐independent transformation in MLL‐CSCs derived from hematopoietic stem cell (HSC)‐enriched LSK population but not myeloid–granulocyte progenitors. Mechanistically, β‐catenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSK‐derived MLL‐CSCs and helps sustain leukemic self‐renewal. Suppression of Hoxa9 sensitizes LSK‐derived MLL‐CSCs to β‐catenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for β‐catenin/Hoxa9 functions in LSK‐derived MLL‐CSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC self‐renewal, but also reveal a novel molecular network mediated by β‐catenin/Hoxa9/Prmt1 in governing leukemic self‐renewal.
date: 2017-11-02
date_type: published
official_url: http://dx.doi.org/10.15252/embj.201797994
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1506715
doi: 10.15252/embj.201797994
language_elements: English
lyricists_name: Barnes, Josephine
lyricists_id: JBARN73
actors_name: Joyce, Sophia
actors_id: SJOYC12
actors_role: owner
full_text_status: public
publication: The EMBO Journal
volume: 36
number: 21
pagerange: 3139-3155
issn: 0261-4189
citation:        Siriboonpiputtana, T;    Zeisig, BB;    Zarowiecki, M;    Fung, TK;    Mallardo, M;    Tsai, CT;    Lau, PNI;                             ... So, CWE; + view all <#>        Siriboonpiputtana, T;  Zeisig, BB;  Zarowiecki, M;  Fung, TK;  Mallardo, M;  Tsai, CT;  Lau, PNI;  Hoang, QC;  Veiga, P;  Barnes, J;  Lynn, C;  Wilson, A;  Lenhard, B;  So, CWE;   - view fewer <#>    (2017)    Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells.                   The EMBO Journal , 36  (21)   pp. 3139-3155.    10.15252/embj.201797994 <https://doi.org/10.15252/embj.201797994>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10052344/1/Barnes_Transcriptional%20memory%20of%20cells%20of%20origin%20overrides%20%CE%B2%E2%80%90catenin%20requirement%20of%20MLL%20cancer%20stem%20cells_AAM.pdf