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

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.

Deregulated Gene Expression Profiles and Regulatory Networks in Adult and Pediatric RUNX1/RUNX1T1-Positive AML Patients

“…The first contained a total of 140 adult AML patients, 7 of which harbored the RUNX1/RUNX1T1 fusion (GEO accession, GSE37642; Platform, GPL570) [ 23 , 24 , 25 , 26 ]. The second contained 16 pediatric AML patients harboring the RUNX1/RUNX1T1 fusion out of a total of 48 AML patients (GSE75461; Platform, GPL17586) [ 27 , 28 ].…”

Non-Coding RNA-Dependent Regulation of Mitochondrial Dynamics in Cancer Pathophysiology

“…Notably, AML patients with the highest CDK6-AS1 levels were at high risk of not achieving complete remission, and also had elevated expression of mitochondrial translation-related genes, while being negatively enriched in genes regulated by RUNX1, an essential factor for the early hematopoietic differentiation process. Functionally, it was proven that CDK6-AS1 depletion promoted the differentiation of CD34 + cells, demonstrating no effect on cell viability, but inducing a reduction in the colony-forming capacity of AML cells [ 78 ].…”

“…Overall, these findings suggest that aberrant expression of CDK6-AS1 maintains more immature leukemic stem cell subsets with elevated mitochondrial activities to address high energy demand, inducing drug resistance and apoptosis escape. CDK6-AS1 expression, correlating with mitochondrial status, could thus allow to discriminate AML patients benefitting from the combination of chemotherapy with mitochondria-targeting agents [ 78 ].…”

Long noncoding RNAs as regulators of pediatric acute myeloid leukemia

“…A recent elaborate study has identified lncRNA CDK6-AS1 as a novel regulator in pediatric AML [ 60 ]. In a pediatric patient cohort, CDK6-AS1 was significantly overexpressed and associated with higher minimal residual disease after induction therapy.…”

“…Interestingly, mitochondrial targeting, using Tigecycline, sensitizes AML blasts with high CDK6-AS1 expression to chemotherapy, supporting the concept of a mitochondrial vulnerability in these blasts. Overall, these findings identified CDK6-AS1 as an important regulator of early hematopoietic differentiation and leukemogenesis of pediatric AML and uncovered therapeutics targeting mitochondrial biogenesis as a novel treatment strategy in pediatric AML [ 60 ].…”