Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells
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ORIGINAL ARTICLE
Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells Kana Nakatani1 · Hidemasa Matsuo1 · Yutarou Harata1 · Moe Higashitani1 · Asami Koyama1 · Mina Noura1 · Yoko Nishinaka‑Arai1,2 · Yasuhiko Kamikubo1 · Souichi Adachi1 Received: 4 August 2020 / Revised: 10 September 2020 / Accepted: 18 September 2020 © Japanese Society of Hematology 2020
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. Keywords Acute myeloid leukemia · t(8;21) · Cyclin D2 · CDK4/6 · Autophagy
Introduction Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease [1]. t(8;21))(q22;q22)/RUNX1RUNX1T1 [also known as AML1-ETO, hereafter referred to as t(8;21)] is one of the most frequent cytogenetic abnormalities in AML. The incidence of t(8;21) is 12–14% in Kana Nakatani and Hidemasa Matsuo contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-03015-4) contains supplementary material, which is available to authorized users. * Souichi Adachi [email protected]‑u.ac.jp 1
Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Kawahara‑cho, Shogoin, Sakyoku, Kyoto 606‑8507, Japan
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
2
pediatric AML and approximately 7% in adult AML [2–6]. Although t(8;21) AML patients have a more favorable prognosis than other cytogenetic subgroups, nearly 40% of t(8;21) AML patients experience relapse [7–10]. Therefore, novel therapeutic approaches based on a better unde
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