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

Tiansu Wang, Allison R. Pine, Andriana G. Kotini, Han Yuan, Lee Zamparo, Daniel T. Starczynowski, Christina Leslie, Eirini P. Papapetrou

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Pages (from-to)1074-1089.e7
JournalCell Stem Cell
Volume28
Issue number6
DOIs
StatePublished - 3 Jun 2021

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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