Intra‐heterogeneity in transcription and chemoresistant property of leukemia‐initiating cells in murine Setd2 −/− acute myeloid leukemia

作者：Jiachun Song, Longting Du, Ping Liu, Fuhui Wang, Bo Zhang, Yinyin Xie, Jing Lu, Yi Jin, Yan Zhou, Gang Lv, Jianmin Zhang, Sai‐Juan Chen, Chen Zhu, Xiao‐Jian Sun, Yuanliang Zhang, Qiuhua Huang · 发表于：癌症：英文版 · 年份：2021 · DOI：10.1002/cac2.12189 · 被引用次数：13 · 研究领域：Acute Myeloid Leukemia Research、Immune cells in cancer、Single-cell and spatial transcriptomics

Abstract Background Heterogeneity of leukemia‐initiating cells (LICs) is a major obstacle in acute myeloid leukemia (AML) therapy. Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML. However, the functional heterogeneity including the drug response of coexistent LICs remains unclear. Therefore, this study aimed to clarify the intra‐heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments. Methods Spleen cells from the primary Setd2 −/− ‐AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model. Flow cytometry was used to analyze the immunophenotype of the leukemic mice. Whole‐genome sequencing was conducted to detect secondary hits responsible for leukemia transformation. A serial transplantation assay was used to determine the self‐renewal potential of Setd2 −/− ‐AML cells. A limiting‐dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells. Bulk and single‐cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs. Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs. Results In this study, we observed an aged Setd2 −/− mouse developing AML with co‐mutation of Nras G12S and Braf K520E . Further investigation identified two ...