Acute myeloid leukemia iPSCs reveal a role for RUNX1 in the maintenance of human leukemia stem cells Journal Article

   


Authors: Wesely, J.; Kotini, A. G.; Izzo, F.; Luo, H.; Yuan, H.; Sun, J.; Georgomanoli, M.; Zviran, A.; Deslauriers, A. G.; Dusaj, N.; Nimer, S. D.; Leslie, C.; Landau, D. A.; Kharas, M. G.; Papapetrou, E. P.
Article Title: Acute myeloid leukemia iPSCs reveal a role for RUNX1 in the maintenance of human leukemia stem cells
Abstract: Wesely et al. report that AML-iPSC-derived hematopoietic cells are hierarchically organized and contain cells with hallmark features of LSCs (iLSCs). Through integrative genomic studies of bulk and single-cell transcriptomes and chromatin accessibility, they derive a LSC gene signature and identify RUNX1 as an AML LSC dependency with therapeutic implications. © 2020 The Authors Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs. © 2020 The Authors
Keywords: cancer survival; clinical article; controlled study; human cell; nonhuman; prospective study; protein function; animal cell; mouse; animal tissue; animal experiment; animal model; genotype; cell differentiation; in vitro study; molecular cloning; chromatin; leukemia cell; cancer stem cell; cell fractionation; hematopoietic cell kinase; transcriptome; tumor engraftment; transcription factor runx1; transcriptome sequencing; aml; acute myeloid leukemia; ipscs; xenotransplantation; induced pluripotent stem cell; gene knockdown; human; female; priority journal; article; runx1; leukemia stem cells; ilscs; lsc gene signature
Journal Title: Cell Reports
Volume: 31
Issue: 9
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2020-06-02
Start Page: 107688
Language: English
DOI: 10.1016/j.celrep.2020.107688
PUBMED: 32492433
PROVIDER: scopus
PMCID: PMC7786450
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085563442&doi=10.1016%2fj.celrep.2020.107688&partnerID=40&md5=a8d93274d4d28946686131567e66aa6a
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
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MSK Authors
  1. Christina Leslie
    187 Leslie
  2. Michael Kharas
    96 Kharas
  3. Han Yuan
    8 Yuan
  4. Hanzhi Luo
    22 Luo
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