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Research ArticleHematology
Open Access | 
10.1172/JCI172468
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Luo, Y. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Feng, X. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Lang, W. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Xu, W. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Wang, W. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Mei, C. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Ye, L. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Zhu, S. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Wang, L. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Zhou, X. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Zeng, H. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Ma, L. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Ren, Y. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Jin, J. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Xu, R. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
Find articles by Huang, G. in: JCI | PubMed | Google Scholar
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, Texas, USA.
3Stanford Genome Technology Center, Palo Alto, California, USA.
4Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
5Department of Pediatrics, Peking University People’s Hospital, Beijing, China.
6Department of Hematology, The Second Affiliated Hospital, School of Medicine,
7Cancer Center, and
8Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Address correspondence to: Hongyan Tong, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China 310012. Phone: 86.57187235589; Email: tonghongyan@zju.edu.cn. Or to: Gang Huang, Department of Cell Systems and Anatomy, Department of Pathology and Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health, STRF Bld., Room 236.3, MC 8262 Box #14, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA. Phone: 210.450.7061; Email: huangg1@uthscsa.edu. Or to: Rongzhen Xu, Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Rd., Shangcheng District, Hangzhou, Zhejiang, China, 310009. Phone: 86.57187315242; Email: zrxyk10@zju.edu.cn.
Authorship note: YL, XF, and WL contributed equally to this work.
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Authorship note: YL, XF, and WL contributed equally to this work.
Published February 22, 2024 - More info
Published in Volume 134, Issue 8 on April 15, 2024
AbstractChromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.
Graphical Abstract
Introduction
Myelodysplastic syndromes (MDS) refer to a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis and morphological dysplasia (1). Recent studies indicate that up to 14%–25% of patients with de novo MDS harbor a complex karyotype (CK) during initial cytogenetic evaluation (2–4). CK, which refers to 3 or more independent chromosomal abnormalities identified by several complementary techniques, is well established as a poor risk factor for patients with MDS, resulting in a poor prognosis and progression of treatment-related secondary MDS (t-MDS) (5, 6). In recent years, most studies have focused on the associations of TP53 mutation or deactivation with CK (7–9). Hitherto, besides TP53, few genes were reported to be associated with cytogenetic aberration in MDS (10, 11).
ONECUT3 belongs to the ONECUT family, an ancient homeobox transcription factor (TF) superfamily (12). To date, research on ONECUT3 has focused on the physiological regulation of embryo development, while the roles of ONECUT3 in cancer remain poorly understood (13–15). From our consolidated clinical data, high levels of ONECUT3 are positively associated with CK incidences in WT TP53 MDS. Given that a single TF can modulate multiple downstream genes, ONECUT3, a potential master TF of MDS with CK, could be targeted for more effective MDS therapy, especially aggressive MDS.
To fill this knowledge gap, we conducted RNA-Seq to find the CK-associated TF, which showed that ONECUT3 was upregulated in MDS with CK, independent of TP53 mutation. Intriguingly, ONECUT3 predicted poor survival of patients with MDS. Overexpression (OE) of ONECUT3 induced the enrichment of the mitosis process–related genes INCENP and CDCA8, as ONECUT3 bound to genomic regions of INCENP and CDCA8, driving mitotic defects and leading to multinucleation and an aberrant karyotype. Importantly, high ONECUT3 levels were associated with poor sensitivity to chemotherapy, suggesting that ONECUT3-targeted therapy may benefit the chemosensitization of MDS patients with CK. Our study provided the evidence of ONECUT3 as a TF and regulator in MDS with CK, revealing ONECUT3 as a potential therapeutic target for patients with MDS.
ResultsHigh ONECUT3 expression is correlated with CK in MDS. To identify potential master transcriptional regulators associated with CK in MDS, we performed differential analysis of RNA-Seq (CK vs. normal karyotype [NK]). Of note, these patients were WT for TP53 (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI172468DS1). TFs with highly aberrant expression were screened from the top 100 upregulated genes (Figure 1A and Supplemental Table 2), and ONECUT3 was found to be expressed at low levels in normal bone marrow (BM) cells (Figure 1A and Supplemental Figure 1, A and B). High ONECUT3 expression levels were identified as a predictor of poor overall survival (OS) in univariable and multivariable analyses (Figure 1, B and C, and Supplemental Table 3).
Figure 1A high level of the TF ONECUT3 is correlated with a CK in MDS. (A) Schematic illustration of paired RNA-Seq to find the potential transcription regulator for a CK. (i) RNA-Seq was performed on RNA samples from 5 paired patients with MDS with a CK or a NK. Each sample was matched for sex, age, and BM blasts (Supplemental Table 1). (ii) Volcano map showed the differential expression genes. Blue dots represent downregulated genes in the CK versus the NK (P < 0.05); orange dots represent upregulated genes (P < 0.05, log2 fold change [FC] <4.7 in CK); and red dots indicate the top 100 upregulated genes (P < 0.05, log2 FC >4.7) in Supplemental Table 2. (iii) Functional enrichment analysis of the top 100 upregulated genes by Metascape (metascape.org). (iv) Heatmap visualization of the mRNA abundance (normalized to fragments per kilobase per million mapped reads [FPKM]) for 6 TFs among the top 100 genes. (v) Only ONECUT3 was expressed at relatively low levels in the BM samples (see Supplemental Figure 1, A and B). (B–D) Quantitative real-time PCR was performed to measure mRNA levels of ONECUT3 in 165 MDS patients harboring WT TP53 with different cytogenetic aberrations and 31 volunteers. The mean value ± 1 SD for the healthy donor was used as a cutoff. (B) Kaplan-Meier survival curves showing the OS of patients with low or high expression of ONECUT3. (C) The forest plot was generated based on the multivariable analysis of factors associated with OS. (D) Each data point represents ONECUT3 expression for an individual patient. RQ, relative quantification. (E) Western blot analysis was applied to detect endogenous ONECUT3 expression using a homemade antibody (Supplemental Figure 1, C and D). A positive control (Ctrl) was achieved by transfecting HEK293T cells with pcDNA3.1-hONECUT3 for 48 hours. The lysate was from the BM mononuclear cells of MDS patients with a CK (P1 and P2), a NK (P3 and P4), and 2 volunteer donors of HSPCs (D1 and D2). (F) ONECUT3 MFI detected by flow cytometry (see gating strategy in Supplemental Figure 1E) in CD34+CD38– (left panel) and CD34+CD38+ (right panel) of BM mononuclear cells from volunteer donors of HSPCs (n = 14), MDS patients with a NK (n = 8), and MDS patients with an aberrant karyotype (1–2 cytogenetic aberrations, n = 8; CK, n = 6). Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (D and F). *P < 0.05, **P < 0.01, and ***P < 0.001, and ****P < 0.0001.
We subsequently expanded the sample size to address the relationship between ONECUT3 expression and a CK (n = 165). mRNA levels of ONECUT3 were correlated with chromosomal karyotype grouping (P = 0.009) (Supplemental Table 4). ONECUT3 abundance gradually increased in the following groups: healthy volunteers, MDS patients with a NK, MDS patients with 1 cytogenetic aberration, MDS patients with 2 cytogenetic aberrations, and MDS patients with a CK (highest) (Figure 1D). Additionally, we conducted a correlation analysis between recurrently mutated genes in MDS and ONECUT3 levels (Supplemental Table 5) and noted a correlation between high expression levels of ONECUT3 and mutant PHF6 (P = 0.029), WT IDH2 (P = 0.018), and WT KMT2D (P = 0.033).
To further assess whether high ONECUT3 protein levels correlated with CK, we generated the rabbit anti-ONECUT3 antibody with high specificity (Supplemental Figure 1, C and D). First, we applied Western blot analysis to detect endogenous ONECUT3 expression in BM mononuclear cells from patients with MDS. ONECUT3 protein expression was detected at high levels in CK and at relatively lower levels in NK, followed by levels in healthy volunteers (Figure 1E). In addition, flow cytometry showed a high abundance of ONECUT3 in BM hematopoietic stem/progenitor cells (HSPCs) (CD34+CD38– and CD34+CD38+) from patients with MDS with an aberrant karyotype compared with its expression in patients with MDS with a NK and the healthy donor group (Figure 1F and Supplemental Figure 1E). These data indicated that a high abundance (protein and mRNA) of ONECUT3 was correlated with a CK in MDS.
ONECUT3 OE leads to multinucleation and a CK independent of TP53. On the basis of the above clinical findings, we then investigated the effect of ONECUT3 OE on TP53-independent karyotype formation. To begin, WT Tp53 and Tp53-KO mouse embryonic fibroblasts (MEFs) were generated from the related E13.5 embryos obtained from heterozygotic breeding (Figure 2A). Then, enforced Onecut3 expression was induced by the tetracycline-inducible retroviral gene expression system (Retro-X Tet-One inducible expression system) in both WT Tp53 and Tp53-KO MEFs. After 48 hours of doxycycline (Dox) treatment, both WT Tp53 and Tp53-KO MEFs exhibited Onecut3 OE, indicating that inducible ONECUT3-overexpressing stable MEFs were successfully generated (Figure 2B). Importantly, ONECUT3 OE gave rise to more multinucleated variants, hyperdiploid cells, and aberrant chromosome numbers in both WT Tp53 and Tp53-KO MEFs when compared with those without Dox induct
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