Patients with acute myeloid leukemia (AML) carryinghigh-riskgenetic 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 sub-groupwith 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.

Porcù, E., Benetton, M., Bisio, V., Da Ros, A., Tregnago, C., Borella, G., et al. (2021). The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics. ISCIENCE, 24(11), 103350 [10.1016/j.isci.2021.103350].

The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics

Bordi, Matteo;Campello, Silvia;
2021-11-19

Abstract

Patients with acute myeloid leukemia (AML) carryinghigh-riskgenetic 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 sub-groupwith 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.
19-nov-2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06 - ANATOMIA COMPARATA E CITOLOGIA
English
Cancer
Cell biology
Molecular biology
Porcù, E., Benetton, M., Bisio, V., Da Ros, A., Tregnago, C., Borella, G., et al. (2021). The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics. ISCIENCE, 24(11), 103350 [10.1016/j.isci.2021.103350].
Porcù, E; Benetton, M; Bisio, V; Da Ros, A; Tregnago, C; Borella, G; Zanon, C; Bordi, M; Germano, G; Manni, S; Campello, S; Rao, Ds; Locatelli, F; Pi...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/292107
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