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The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics
- Source :
- iScience, Vol 24, Iss 11, Pp 103350-(2021), iScience, iScience, vol 24, iss 11
- Publication Year :
- 2021
- Publisher :
- CELL PRESS, 2021.
-
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.<br />Graphical abstract<br />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<br />Molecular biology; Cell biology; Cancer
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- iScience, Vol 24, Iss 11, Pp 103350-(2021), iScience, iScience, vol 24, iss 11
- Accession number :
- edsair.doi.dedup.....b06df0b093a3b7bd963c768b4676c964