Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
Kuangguo Zhou,
Mi Zhou,
Ling Cheng,
Xing Chen,
Xiaomin Wang,
Yajing Chu,
Qilin Yu,
Shu Zhang,
Na Wang,
Lei Zhao,
Di Wang,
Liang Huang,
Congyi Wang,
Weiping Yuan,
Jianfeng Zhou
Affiliations
Kuangguo Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Mi Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Ling Cheng
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xing Chen
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xiaomin Wang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Yajing Chu
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Qilin Yu
The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Shu Zhang
The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Na Wang
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Lei Zhao
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Di Wang
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Liang Huang
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Congyi Wang
The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Weiping Yuan
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Jianfeng Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Abstract Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.
