2. Academic Validation
  3. Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets

Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets

  • Cell Stem Cell. 2021 Jun 3;28(6):1074-1089.e7. doi: 10.1016/j.stem.2021.01.011.
Tiansu Wang 1,  Allison R Pine 2,  Andriana G Kotini 1,  Han Yuan 2,  Lee Zamparo 2,  Daniel T Starczynowski 3,  Christina Leslie 4,  Eirini P Papapetrou 5
Affiliations

Affiliations

  • 1 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.
  • 2 Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 4 Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
PMID: 33571445 DOI: 10.1016/j.stem.2021.01.011
Abstract

Human cancers arise through the sequential acquisition of somatic mutations that create successive clonal populations. Human Cancer evolution models could help illuminate this process and inform therapeutic intervention at an early disease stage, but their creation has faced significant challenges. Here, we combined induced pluripotent stem cell (iPSC) and CRISPR-Cas9 technologies to develop a model of the clonal evolution of acute myeloid leukemia (AML). Through the stepwise introduction of three driver mutations, we generated iPSC lines that, upon hematopoietic differentiation, capture distinct premalignant stages, including clonal hematopoiesis (CH) and myelodysplastic syndrome (MDS), culminating in a transplantable leukemia, and recapitulate transcriptional and chromatin accessibility signatures of primary human MDS and AML. By mapping dynamic changes in transcriptomes and chromatin landscapes, we characterize transcriptional programs driving specific transitions between disease stages. We identify cell-autonomous dysregulation of inflammatory signaling as an early and persistent event in leukemogenesis and a promising early therapeutic target.

Keywords

AML; IRAK1 inhibitor; IRAK4 inhibitor; UBE2N inhibitor; clonal evolution; gene editing; hematopoietic stem/progenitor cells; inflammatory response; innate immunity; leukemogenesis.

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