RRC ID |
62621
|
著者 |
Nakatani K, Matsuo H, Harata Y, Higashitani M, Koyama A, Noura M, Nishinaka-Arai Y, Kamikubo Y, Adachi S.
|
タイトル |
Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells.
|
ジャーナル |
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.
|
巻・号 |
113(2)
|
ページ |
243-253
|
公開日 |
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
|
リソース情報 |
遺伝子材料 |
pENTR4-H1tetOx1 (RDB07916) |
ヒト・動物細胞 |
THP-1(RCB1189) |