RRC ID 62621
Author Nakatani K, Matsuo H, Harata Y, Higashitani M, Koyama A, Noura M, Nishinaka-Arai Y, Kamikubo Y, Adachi S.
Title Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells.
Journal Int J Hematol
Abstract The t(8;21) translocation is the most common cytogenetic abnormality in acute myeloid leukemia (AML). Although t(8;21) AML patients have a relatively favorable prognosis, relapse is a frequent occurrence, underscoring the need to develop novel therapeutic approaches. Here, we showed that t(8;21) AML is characterized by frequent mutation and overexpression of CCND2. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for the selective CDK4/6 inhibitors palbociclib and abemaciclib than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. CDK4/6 inhibition decreased MAP-ERK and PI3K-AKT-mTOR signaling pathway activity, induced LC3B-I to LC3B-II conversion, and enhanced autophagosome formation, suggesting autophagy induction. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with the CDK4/6 inhibitor abemaciclib significantly increased the percentage of apoptotic (Annexin V positive) cells, whereas CQ or LY294002 single treatment had no significant effects. The effectiveness of co-inhibiting CDK4/6 and autophagy was confirmed in primary t(8;21) AML cells. The results suggest that the combination of CDK4/6 and autophagy inhibitors had a synergistic effect on inducing apoptosis, suggesting a novel therapeutic approach for the treatment of t(8;21) AML.
Volume 113(2)
Pages 243-253
Published 2021-2-1
DOI 10.1007/s12185-020-03015-4
PII 10.1007/s12185-020-03015-4
PMID 33068248
MeSH Apoptosis / genetics* Autophagy / genetics* Cell Line, Tumor Cell Proliferation / drug effects Chromosomes, Human, Pair 21 Chromosomes, Human, Pair 8 Cyclin D2 / genetics Cyclin-Dependent Kinase 4 / antagonists & inhibitors* Cyclin-Dependent Kinase 4 / genetics Cyclin-Dependent Kinase 6 / antagonists & inhibitors* Cyclin-Dependent Kinase 6 / genetics Gene Expression Gene Expression Regulation, Leukemic / drug effects Humans Leukemia, Myeloid, Acute / drug therapy Leukemia, Myeloid, Acute / genetics* Leukemia, Myeloid, Acute / metabolism Mutation Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use RNA Interference Signal Transduction / drug effects Translocation, Genetic*
IF 2.245
DNA material pENTR4-H1tetOx1 (RDB07916)
Human and Animal Cells THP-1(RCB1189)