1. The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics
- Author
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Martina Pigazzi, Ambra Da Ros, Elena Porcù, Sabrina Manni, Maddalena Benetton, Dinesh S. Rao, Franco Locatelli, Claudia Tregnago, Giulia Borella, Matteo Bordi, Silvia Campello, Carlo Zanon, Giuseppe Germano, and Valeria Bisio
- Subjects
Cell biology ,Myeloid ,Settore BIO/06 ,Childhood Leukemia ,Pediatric Cancer ,Cancer ,Molecular biology ,Science ,CD34 ,Biology ,Article ,chemistry.chemical_compound ,Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,hemic and lymphatic diseases ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Gene silencing ,Aetiology ,Pediatric ,Multidisciplinary ,Myeloid leukemia ,Hematology ,Stem Cell Research ,medicine.disease ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,RUNX1 ,chemistry ,Cancer research ,Cytarabine ,medicine.drug - Abstract
Summary Patients 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 RNA CDK6-AS1 able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. CDK6-AS1 silencing 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. By CDK6-AS1 silencing in 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 high CDK6-AS1 levels, supporting the concept of a mitochondrial vulnerability. Together, these findings uncover CDK6-AS1 as crucial in myeloid differentiation and mitochondrial mass regulation., Graphical abstract, Highlights • CDK6-AS1 acts in concert with CDK6 • High CDK6-AS1 levels trigger RUNX1 early differentiation arrest in myeloid cells • CDK6-AS1 controls mitochondrial mass of AML blasts • CDK6-AS1 levels impact on mitochondrial-targeted agents sensitivity, Molecular biology; Cell biology; Cancer
- Published
- 2021