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.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA.
Cell Rep. 2020 Jun 2;31(9):107688. doi: 10.1016/j.celrep.2020.107688.
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.
白血病干细胞（LSCs）被认为比大量急性髓细胞白血病（AML）细胞具有更明显的脆弱性，但由于其稀有性以及缺乏用于其预期分离的通用标记物，阻碍了对其的研究。我们报告称，源自 AML 患者的遗传克隆诱导多能干细胞（iPSC）具有极高的植入潜力，并在造血分化后产生表型层次结构。通过命运追踪实验、异种移植和单细胞转录组学，我们鉴定出一个可以通过体外贴壁生长的方式进行前瞻性分离的细胞群（iLSC），该细胞群位于该层次结构的顶端，并且具有 LSC 的标志性特征。通过整合 iLSC 转录组和染色质景观的基因组研究，我们得出了一个 LSC 基因特征，可以预测患者的生存情况，并揭示了 AML 基因型中 LSCs 对 RUNX1 转录因子的依赖性。这些发现可以为靶向 AML LSCs 的治疗努力提供助力。
