Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells
Josephine Wesely,
Andriana G. Kotini,
Franco Izzo,
Hanzhi Luo,
Han Yuan,
Jun Sun,
Maria Georgomanoli,
Asaf Zviran,
André G. Deslauriers,
Neville Dusaj,
Stephen D. Nimer,
Christina Leslie,
Dan A. Landau,
Michael G. Kharas,
Eirini P. Papapetrou
Affiliations
Josephine Wesely
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Andriana G. Kotini
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Franco Izzo
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA
Hanzhi Luo
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Han Yuan
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Jun Sun
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Maria Georgomanoli
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Asaf Zviran
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA
André G. Deslauriers
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Biotech Research and Innovation Center, University of Copenhagen, Denmark; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Neville Dusaj
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA
Stephen D. Nimer
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Christina Leslie
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Dan A. Landau
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA
Michael G. Kharas
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Corresponding author
Eirini P. Papapetrou
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Corresponding author
Summary: 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.
