The CDK4/6 Inhibitor Palbociclib Synergizes with ATRA to Induce Differentiation in AML

Author:

Hu Linhui1234ORCID,Li Qian123ORCID,Wang Jiyu123ORCID,Wang Huiping123ORCID,Ren Xiyang123ORCID,Huang Keke123ORCID,Wang Yangyang123ORCID,Liang Xue123ORCID,Pu Lianfang123ORCID,Xiong Shudao123ORCID,Zhai Zhimin123ORCID

Affiliation:

1. Hematological Lab, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China. 1

2. Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China. 2

3. Center of Hematology Research, Anhui Medical University, Hefei 230601, Anhui Province, People’s Republic of China. 3

4. Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China. 4

Abstract

Abstract Differentiation therapy based on ATRA almost cured acute promyelocytic leukemia (APL). However, it is disappointing that ATRA is not effective against other acute myeloid leukemia (AML) subtypes. Developing new and effective anti-AML therapies that promote leukemia differentiation is necessary. The CDK4/6-cyclin D pathway is a key initiator of the G1–S phase transition, which determines cell fate. Herein, we investigated whether the CDK4/6 inhibitor palbociclib would synergize with ATRA to promote leukemia differentiation in vitro and in vivo. Our findings revealed that CDK4/6-cyclin D pathway genes were aberrantly expressed in AML, and we observed that palbociclib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation. The combination of palbociclib and ATRA attenuated AML cell expansion in vivo. These enhanced differentiation effects may be associated with the regulation of transcription factors, including RARα, E2F1, and STAT1. Overall, our findings demonstrate that CDK4/6 inhibition sensitizes AML cells to ATRA and could guide the development of novel therapeutic strategies for patients with AML.

Funder

National Natural Science Foundation of China

Anhui Provincial Department of Education

Anhui Medical University

Publisher

American Association for Cancer Research (AACR)

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