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Title: Transcriptional memory of cells of origin overrides β-catenin requirement of MLL cancer stem cells
Authors: Teerapong Siriboonpiputtana
Bernd B. Zeisig
Magdalena Zarowiecki
Tsz Kan Fung
Maria Mallardo
Chiou Tsun Tsai
Priscilla Nga Ieng Lau
Quoc Chinh Hoang
Pedro Veiga
Jo Barnes
Claire Lynn
Amanda Wilson
Boris Lenhard
Chi Wai Eric So
King's College London
Imperial College London
Medical Research Council
Universitetet i Bergen
Mahidol University
Vinmec Research Institute for Stem Cells and Gene Technology
The Institute of Cancer Research, London
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 2-Nov-2017
Citation: EMBO Journal. Vol.36, No.21 (2017), 3139-3155
Abstract: © 2017 The Authors 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.
ISSN: 14602075
Appears in Collections:Scopus 2016-2017

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