文章基本信息

标题：The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics
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作者：Elena Porcù ; Maddalena Benetton ; Valeria Bisio 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-23
DOI：10.1016/j.isci.2021.103350
语种：English
出版社：Elsevier
摘要：SummaryPatients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNACDK6-AS1able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics.CDK6-AS1silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued. This latter phenomenon derived from RUNX1 transcriptional control, responsible for the stemness of hematopoietic precursors and for the block of differentiation in AML. ByCDK6-AS1silencingin vitro,AML mitochondrial mass decreased with augmented pharmacological sensitivity to mitochondria-targeting drugs. In vivo,the combination of tigecycline and cytarabine reduced leukemia progression in the AML-PDX model with highCDK6-AS1levels, supporting the concept of a mitochondrial vulnerability. Together, these findings uncoverCDK6-AS1as crucial in myeloid differentiation and mitochondrial mass regulation.Graphical abstractDisplay OmittedHighlights•CDK6-AS1acts in concert withCDK6•HighCDK6-AS1levels trigger RUNX1 early differentiation arrest in myeloid cells•CDK6-AS1controls mitochondrial mass of AML blasts•CDK6-AS1levels impact on mitochondrial-targeted agents sensitivityMolecular biology; Cell biology; Cancer