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EMBO J. 2017 Nov 2;36(21):3139-3155. doi: 10.15252/embj.201797994. Epub 2017 Oct 4.

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

Author information

1
Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
2
Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, London, UK.
3
Computational Regulatory Genomics, MRC London Institute of Medical Sciences, London, UK.
4
Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway.
5
Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK eric.so@kcl.ac.uk.

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.

KEYWORDS:

Hoxa9; MLL leukemia; Prmt1; Wnt/β‐catenin; cells of origin

PMID:
28978671
PMCID:
PMC5666593
[Available on 2018-11-02]
DOI:
10.15252/embj.201797994
[Indexed for MEDLINE]

Publication type, MeSH terms, Substances, Grant support

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