@article{b17ec5229a8f4d399976427b6299f341,
title = "Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets",
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",
author = "Tiansu Wang and Pine, {Allison R.} and Kotini, {Andriana G.} and Han Yuan and Lee Zamparo and Starczynowski, {Daniel T.} and Christina Leslie and Papapetrou, {Eirini P.}",
note = "Funding Information: We thank Elli Papaemmanuil for advice on mutational selection and assistance with gene panel sequencing of patient samples. This work was supported by US National Institutes of Health (NIH) grants R01HL137219 and R01CA225231, the New York State Stem Cell Board, the Pershing Square Sohn Cancer Research Alliance, the RUNX1 Research Program (RRP)/Alex's Lemonade Stand Foundation (ALSF), United States, and a Scholar Award from the Leukemia and Lymphoma Society (LLS), all to E.P.P.; by NIH grant U54 CA209975 to C.L.; and by NIH grants R35HL135787 and R01DK113639, an LLS Blood Cancer Discovery Grant (8021-20), an LLS Scholar Award, and a CancerFree KIDS grant, all to D.T.S. T.W. was supported by a Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG). A.R.P. was supported by the Tri-Institutional Training Program in Computational Biology and Medicine (CBM) funded by NIH grant 1T32GM083937. T.W. and A.G.K. performed experiments and analyzed data. A.R.P, H.Y. L.Z. and C.L. analyzed RNA-seq and ATAC-seq data. D.T.S. provided research materials and advice. E.P.P. conceived, designed, and supervised the study, analyzed data, and wrote the manuscript with assistance from T.W. and A.G.K. D.T.S. serves on the scientific advisory board of Kurome Therapeutics. E.P.P. has received honoraria from Celgene and Merck and research support from Incyte for research not related to this study. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "3",
doi = "10.1016/j.stem.2021.01.011",
language = "English",
volume = "28",
pages = "1074--1089.e7",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "6",
}