期刊
EMBO JOURNAL
卷 36, 期 21, 页码 3139-3155出版社
WILEY
DOI: 10.15252/embj.201797994
关键词
cells of origin; Hoxa9; MLL leukemia; Prmt1; Wnt/beta-catenin
资金
- Cancer Research UK (CRUK) program [A16753]
- Bloodwise program grant
- Cancer Research UK [16753] Funding Source: researchfish
- Medical Research Council [MC_UP_1102/1, G0800892] Funding Source: researchfish
- MRC [MC_UP_1102/1, G0800892] Funding Source: UKRI
While beta-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 P-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, beta-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 beta-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 beta-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 beta-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.
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