Research ArticleHematology Open Access | 10.1172/JCI173403

Qiong Wu,1,2 Chunjie Yu,2 Fang Yu,2 Yiran Guo,3 Yue Sheng,2 Liping Li,4 Yafang Li,2 Yutao Zhang,2,5 Chao Hu,6 Jue Wang,2 Tong-chuan He,7 Yong Huang,8 Hongyu Ni,9 Zhiguang Huo,5 Wenshu Wu,6 Gang Greg Wang,3 Jianxin Lyu,1,10,11 and Zhijian Qian2

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Wu, Q. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Yu, C. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Yu, F. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Guo, Y. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Sheng, Y. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Li, L. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Li, Y. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Hu, C. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Wang, J. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by He, T. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Huang, Y. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Ni, H. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Huo, Z. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Wu, W. in: JCI | PubMed | Google Scholar

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Wang, G. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Lyu, J. in: JCI | PubMed | Google Scholar |

1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

2Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.

3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

4Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA.

5Department of Biostatistics, University of Florida, Gainesville, Florida, USA.

6Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

7Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA.

8Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

10Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and

11Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China.

Address correspondence to: Jianxin Lyu, 182 Tianmushan Road, Huanglong Campus, Hangzhou Medical College, Hangzhou, Zhejiang, China, 310000. Email: jxlu313@163.com. Or to: Zhijian Qian, 2033 Mowry Road, 285C, Gainesville, Florida, USA, 32608 USA. Email: zhijian.qian@medicine.ufl.edu.

Authorship note: QW, CY, and FY contributed equally to this work.

Find articles by Qian, Z. in: JCI | PubMed | Google Scholar |

Authorship note: QW, CY, and FY contributed equally to this work.

Published December 16, 2024 - More info

Published in Volume 134, Issue 24 on December 16, 2024
J Clin Invest. 2024;134(24):e173403. https://doi.org/10.1172/JCI173403.
© 2024 Wu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published December 16, 2024 - Version history
Received: June 27, 2023; Accepted: October 24, 2024 View PDF Abstract

Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm–like (MDS/MPN–like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.

Introduction

Myelodysplastic syndromes (MDSs) are a group of clonal hematopoietic disorders characterized by abnormal development and maturation of blood cells in bone marrow. These disorders often lead to bone marrow failure, resulting in insufficient production of mature and functional blood cells. The hallmark features of MDS include morphologic dysplasia in one or more blood cell lineages and cytopenias of the peripheral blood (1, 2). This clinical phenotype of MDS is nonspecific and can overlap with various other benign or malignant conditions, such as myeloproliferative neoplasm (MPN). These disorders often exhibit hematopoietic dysplasia with increased proliferation of monocytes, neutrophils, or platelets (1, 3, 4). Approximately 30% of patients diagnosed with MDS ultimately develop acute myeloid leukemia (AML) (5).

Evi1 was first identified as a common site of ecotropic viral integration in mice with retrovirally induced myeloid malignancies (6). The human EVI1 (MECOM) gene is located on chromosome 3q26, and multiple isoforms of EVI1 are encoded in the MECOM locus (7). Rearrangements of chromosome 3q26, which lead to upregulation of EVI1, frequently occur in myeloid malignant diseases including MDS, AML, and chronic myeloid leukemia (CML) (8–10). MDS, AML, and CML with inv(3)/t(3;3) rearrangements often present similar pathological features with poor prognosis (8, 11, 12). It was reported that chromosome rearrangements cause overexpression of EVI1 due to relocation of enhancers, including GATA binding protein 2 (GATA2) enhancer in inv(3)/t(3;3) (q21q26) (13, 14) and MYC super-enhancer in t(3;8) (q26;q24) close to the EVI1 gene (15). EVI1 overexpression can occur in MDS patients without chromosome 3 rearrangements. EVI1 upregulation is detected in approximately 8%–10% of MDS/AML and 30% of advanced CML; however, the mechanism that results in EVI1 overexpression remains unclear (16). Additionally, high expression of EVI1 is also detected in a subgroup of MDS/MPN (17). MDS/AML with EVI1 overexpression often exhibits dysplasia of erythrocyte and megakaryocytic lineages (8, 12, 18).

Evi1 is essential for the maintenance of long-term hematopoietic stem cells (LT-HSCs) in mice (19). Introduction of EVI1 via retroviral expression in hematopoietic stem/progenitor cells (HSPCs) led to the development of MDS in mice, while these mice were unable to develop AML with long latencies (20), suggesting that EVI1 alone is insufficient to induce leukemia in mice. However, other studies also showed that EVI1 overexpression can induce AML in mice (13, 21–23), possibly due to additional mutations resulting from retroviral insertion or prolonged disease progression in mice. Moreover, the degree of EVI1 overexpression in vivo may also contribute to the varying phenotypes observed in mouse models of EVI1 overexpression.

Studies have reported that EVI1 exerts control over cell proliferation, apoptosis, cell differentiation, and the cell cycle of hematopoietic progenitor cells through various mechanisms (24, 25). However, the molecular mechanisms underlying the role of EVI1 overexpression in leukemogenesis in vivo remain incompletely understood, and targeted therapies for MDS/AML patients with EVI1 overexpression are currently lacking.

In this study, we present a novel transgenic mouse model allowing conditional activation of Evi1 expression at low levels in HSPCs. These Evi1-transgenic mice developed a disease resembling myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), characterized by anemia and thrombocytopenia, accompanied by an expansion of myelopoiesis and suppressed lymphopoiesis. Erythroid and megakaryocyte dysplasia was also observed. Further characterization of HSPCs revealed that Evi1 overexpression led to a reduction in HSCs and an expansion of myeloid progenitor cells. Through integrative analysis of gene expression profiling and EVI1 binding sites, we identified lysine demethylase 6b (Kdm6b) as a direct target of Evi1 in primary HSPCs in mice. Further investigations demonstrated that Evi1 regulated Kdm6b-mediated H3K27me3, resulting in the upregulation of multiple genes, including Laptm4b. Both KDM6B and LAPTM4B expression exhibited positive correlations with EVI1 expression in patients with MDS. We observed upregulation of both KDM6B and LAPTM4B in EVI1hi leukemia c