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Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells

Siriboonpiputtana, T; Zeisig, BB; Zarowiecki, M; Fung, TK; Mallardo, M; Tsai, CT; Lau, PNI; ... So, CWE; + view all (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. Green open access

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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.

Type: Article
Title: Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201797994
Publisher version: http://dx.doi.org/10.15252/embj.201797994
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cells Of Origin, Hoxa9, MLL Leukemia, Prmt1, Wnt/Β‐Catenin
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10052344
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