TY - JOUR TI - Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets AU - Wang, Tiansu AU - Pine, Allison R. AU - Kotini, Andriana G. AU - Yuan, Han AU - Zamparo, Lee AU - Starczynowski, Daniel T. AU - Leslie, Christina AU - Papapetrou, Eirini P. T2 - Cell Stem Cell AB - 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. DA - 2021/02/10/ PY - 2021 DO - 10.1016/j.stem.2021.01.011 DP - ScienceDirect J2 - Cell Stem Cell LA - en SN - 1934-5909 UR - https://www.sciencedirect.com/science/article/pii/S1934590921000114 Y2 - 2021/02/10/19:23:56 KW - AML KW - IRAK1 inhibitor KW - IRAK4 inhibitor KW - UBE2N inhibitor KW - clonal evolution KW - gene editing KW - hematopoietic stem/progenitor cells KW - inflammatory response KW - innate immunity KW - leukemogenesis ER -