Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence.
Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence.
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DOI：
10.1158/2159-8290.cd-20-1375
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发表时间：
2021-06
期刊：
影响因子：
28.2
通讯作者：
Melnick AM
中科院分区：
文献类型：
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作者：
Duy C;Li M;Teater M;Meydan C;Garrett-Bakelman FE;Lee TC;Chin CR;Durmaz C;Kawabata KC;Dhimolea E;Mitsiades CS;Doehner H;D'Andrea RJ;Becker MW;Paietta EM;Mason CE;Carroll M;Melnick AM
急性髓系白血病（AML）患者在化疗后经常复发，但AML复发的机制尚未完全清楚。在此，我们表明，原代AML细胞在体外和体内化疗后进入衰老样表型。这伴随着衰老/炎症和胚胎滞育转录程序的诱导，以及MYC和白血病干细胞基因的下调。单细胞RNA-seq表明白血病干细胞在体外和体内的耗竭，以及具有不同衰老样细胞的亚群的富集。这种衰老效应是短暂的，并赋予上级的集落形成和移植潜力。进入这种衰老样表型依赖于ATR，ATR抑制剂严重损害AML细胞的持久性。总之，我们认为AML复发是由衰老样弹性表型促进的，无论其干细胞状态如何。在恢复后，这些衰老后AML细胞产生具有增加的干细胞潜能的复发AML。
Acute myeloid leukemia (AML) patients frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential.