Structural maintenance of chromosomes 4 is required for leukemia stem cell maintenance in MLL-AF9 induced acute myeloid leukemia

Luyun PengDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Yuanting TangDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Yingchi ZhangState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

Siqi GuoDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Leiwen PengDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Lei YeDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Yuefang WangDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China;

Yongmei JiangDepartment of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China; ;Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China; Correspondence[email protected]

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Abstract

The gene, structural maintenance of chromosomes 4 (SMC4) plays important role in chromosomes condensing and mitotic sister chromatid segregation, which has been revealed in regulating multiple cancer development and carcinogenesis. However, the role of SMC4 in acute myeloid leukemia (AML) propagation and its function in regulation of leukemia stem cells (LSCs) is not yet clear. Using an MLL-AF9 induced AML mouse model, we demonstrated that down modulating of SMC4 expression could prolong the survival time of AML mice. Furthermore, we found that knockdown SMC4 expression decreased the proportion of LSCs and affected its leukemia-initiating capacity. Cell cycle assay demonstrated that more LSCs were arrested in G0 phase by SMC4 knockdown. This activity was accompanied by increased expression of the Cdkn1a (P21) and Cdkn1b (P27) as well as decreased expression of CDK4. Therefore, our study revealed the critical role of SMC4 during AML progression and provided new insights into the mechanism of LSC maintenance.

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Structural maintenance of chromosomes 4 is required for leukemia stem cell maintenance in MLL-AF9 induced acute myeloid leukemia

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Structural maintenance of chromosomes 4 is required for leukemia stem cell maintenance in MLL-AF9 induced acute myeloid leukemia

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